5-6 to 5-7 Heterobicycles as factor Xa inhibitors

ABSTRACT

The present application describes 5-6 or 5-7 heterobicyclics of Formula I: 
                 
 
or pharmaceutically acceptable salt forms thereof, wherein ring P is a 5-membered heteroaromatic and ring M is a 6 or 7-membered non-aromatic carbocycle or heterocycle. Compounds of the present invention are useful as inhibitors of trypsin-like serine proteases, specifically factor Xa.

FIELD OF THE INVENTION

This invention relates generally to 5-6 or 5-7 heterobicycles, which areinhibitors of trypsin-like serine protease enzymes, especially factorXa, pharmaceutical compositions containing the same, and methods ofusing the same as anticoagulant agents for treatment and prevention ofthromboembolic disorders.

BACKGROUND OF THE INVENTION

WO94/20460 describes angiotensin II compounds of the following formula:

wherein X can be a number of substituents and Het can be anitrogen-containing heterobicycle. However, WO94/20460 does not suggestFactor Xa inhibition or exemplify compounds like those of the presentinvention.

WO96/12720 depicts phosphodiesterase type IV and TNF productioninhibitors of the following formula:

wherein X can be oxygen and R² and R³ can a number of substituentsincluding heterocycle, heterocycloalkyl, and phenyl. However, thepresently claimed compounds do not correspond to the compounds ofWO96/12720. Furthermore, WO96/12720 does not suggest Factor Xainhibition.

WO98/52948 details inhibitors of ceramide-mediated signal transduction.One of the types of inhibitors described is of the following formula:

wherein Y₁ can be N—R₆, R₆ can be unsubstituted aryl-alkyl orunsubstituted heterocyclic-alkyl and R₁ can be a substituted aryl group.W098/52948 does not mention factor Xa inhibition or show compounds likethose of the present invention.

U.S. Pat. Nos. 3,365,459, 3,340,269, and 3,423,414 illustrateanti-inflammatory inhibitors of the following formula:

wherein A is 2-3 carbon atoms, X can be O, and R¹ and R³ can besubstituted or unsubstituted aromatic groups. None of these patents,however, exemplify or suggest compounds of the present invention.

WO99/32477 reports Factor Xa inhibitors of the following formula:

wherein the inhibitors contain at least three aryl or heterocyclicgroups (i.e., C, B, and R³) separated by two linking groups (i.e., E andD). Compounds of this sort are not considered to be part of the presentinvention.

WO00/39131 describes heterobicyclic Factor Xa inhibitors of which thefollowing is an example formula:

wherein Z is C or N, G is a mono- or bicyclic group, A is a cyclicmoiety and B is a basic group or a cyclic moiety. Compounds with thissubstitution pattern are not considered to be part of the presentinvention.

WO01/19798 describes factor Xa inhibitors of the following formula:A-Q-D-E-G-J-Xwherein A, D, G, and X can be phenyl or heterocycle. However, none ofthe presently claimed compounds are exemplified or suggested inWO01/19798.

Activated factor Xa, whose major practical role is the generation ofthrombin by the limited proteolysis of prothrombin, holds a centralposition that links the intrinsic and extrinsic activation mechanisms inthe final common pathway of blood coagulation. The generation ofthrombin, the final serine protease in the pathway to generate a fibrinclot, from its precursor is amplified by formation of prothrombinasecomplex (factor Xa, factor V, Ca²⁺ and phospholipid). Since it iscalculated that one molecule of factor Xa can generate 138 molecules ofthrombin (Elodi, S., Varadi, K.: Optimization of conditions for thecatalytic effect of the factor IXa-factor VIII Complex: Probable role ofthe complex in the amplification of blood coagulation. Thromb. Res.1979, 15, 617-629), inhibition of factor Xa may be more efficient thaninactivation of thrombin in interrupting the blood coagulation system.

Therefore, efficacious and specific inhibitors of factor Xa are neededas potentially valuable therapeutic agents for the treatment ofthromboembolic disorders. It is thus desirable to discover new factor Xainhibitors.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novelheterobicycles that are useful as factor Xa inhibitors orpharmaceutically acceptable salts or prodrugs thereof.

It is another object of the present invention to provide pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

It is another object of the present invention to provide a method fortreating thromboembolic disorders comprising administering to a host inneed of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention or a pharmaceuticallyacceptable salt or prodrug form thereof.

It is another object of the present invention to provide a novel methodof treating a patient in need of thromboembolic disorder treatment,comprising: administering a compound of the present invention or apharmaceutically acceptable salt form thereof in an amount effective totreat a thromboembolic disorder

It is another object of the present invention to provide a novel method,comprising: administering a compound of the present invention or apharmaceutically acceptable salt form thereof in an amount effective totreat a thromboembolic disorder.

It is another object of the present invention to provide novel compoundsfor use in therapy.

It is another object of the present invention to provide the use ofnovel compounds for the manufacture of a medicament for the treatment ofa thromboembolic disorder.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat the presently claimed bicyclic compounds, or pharmaceuticallyacceptable salt or prodrug forms thereof, are effective factor Xainhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[1] Thus, in an embodiment, the present invention provides a novelcompound of formula I:

-   or a stereoisomer or pharmaceutically acceptable salt thereof,    wherein;-   ring M, including M₁ and M₂, is a 6 or 7 membered carbocycle or 6 or    7 membered heterocycle, consisting of: carbon atoms and 0-3    heteroatoms selected from 0, S(O)_(p), N, and NZ²;-   ring M is substituted with 0-2 R^(1a) and 0-2 carbonyl groups, and,    comprises: 0-2 double bonds;-   alternatively, M₁ is C(O) or CH₂, M₂ is N, and the bridging portion    of ring M is S(O)₂;-   ring P, including P₁, P₂, P₃, and P₄ is selected from group:-   one of P₄ and M₃ is -Z-A-B and the other -G₁-G;-   G is a group of formula IIa or IIb:-   ring D, including the two atoms of Ring E to which it is attached,    is a 5-6 membered non-aromatic ring consisting of carbon atoms, 0-1    double bonds, and 0-2 heteroatoms selected from the group consisting    of N, O, and S(O)_(p), and D is substituted with 0-2 R;-   alternatively, ring D, including the two atoms of Ring E to which it    is attached, is a 5-6 membered aromatic system consisting of carbon    atoms and 0-2 heteroatoms selected from the group consisting of N,    O, and S(O)_(p), and D is substituted with 0-2 R;-   E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and    pyridazinyl, and is substituted with 1-2 R;-   alternatively, the bridging portion of ring D is absent, and ring E    is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,    pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl,    thienyl, and thiazolyl, and ring E is substituted with 1-2 R;-   alternatively, the bridging portion of ring D is absent, ring E is    selected from phenyl, phenyl, pyridyl, pyrimidyl, pyrazinyl,    pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl,    triazolyl, thienyl, and thiazolyl, and ring E is substituted with 1    R and with a 5-6 membered heterocycle consisting of: carbon atoms    and 1-4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p), wherein the heterocycle is substituted with 0-1 carbonyls,    1-2 R, and having 0-3 ring double bonds;-   R is selected from H, C₁₋₄ alkyl, F, Cl, Br, I, OH, OCH₃, OCH₂CH₃,    OCH(CH₃)₂, OCH₂CH₂CH₃, CN, C(═NR⁸)NR⁷R⁹, NHC(═NR⁸)NR⁷R⁹,    NR⁸CH(═NR⁷), NH₂, NH(C₁₋₃ alkyl), N(C₁₋₃ alkyl)₂, C(═NH)NH₂, CH₂NH₂,    CH₂NH(C₁₋₃ alkyl), CH₂N(C₁₋₃ alkyl)₂, CH₂CH₂NH₂, CH₂CH₂NH(C₁₋₃    alkyl), CH₂CH₂N(C₁₋₃ alkyl)₂, (CR⁸R⁹)_(t)C(O)H,    (CR⁸R⁹)_(t)C(O)R^(2c), (CR⁸R⁹)_(t)NR⁷R⁸, (CR⁸R⁹)_(t)C(O)NR⁷R⁸,    (CR⁸R⁹)_(t)NR⁷C(O)R⁷, (CR⁸R⁹)_(t)OR³, (CR⁸R⁹)_(t)S(O)_(p)NR⁷R⁸,    (CR⁸R⁹)_(t)NR⁷S(O)_(p)R⁷, (CR⁸R⁹)_(t)SR³, (CR⁸R⁹)_(t)S(O)R³,    (CR⁸R⁹)_(t)S(O)₂R³, and OCF₃, provided that S(O)_(p)R⁷ forms other    than S(O)₂H or S(O)H;-   alternatively, when 2 R groups are attached to adjacent atoms, they    combine to form methylenedioxy or ethylenedioxy;-   A is selected from:

C₃₋₁₀ carbocycle substituted with 0-2 R⁴, and

5-12 membered heterocycle consisting of: carbon atoms and 1-4heteroatoms selected from the group consisting of N, O, and S(O)_(p)substituted with 0-2 R⁴;

-   B is selected from: Y, X—Y, (CH₂)₀₋₂C(O)NR²R^(2a),    (CH₂)₀₋₂NR²R^(2a), C(═NR²)NR²R^(2a), and NR²C(═NR²)NR²R^(2a),    provided that Z and B are attached to different atoms on A;-   G₁ is absent or is selected from (CR³R^(3a))₁₋₅,    (CR³R^(3a))₀₋₂CR³═CR³ (CR³R^(3a))₀₋₂, (CR³R^(3a))₀₋₂, C≡C    (CR³R^(3a))₀₋₂, (CR³R^(3a))_(u)C(O) (CR³R^(3a))_(w),    (CR³R^(3a))_(u)C(O)O(CR³R^(3a))_(w),    (CR³R^(3a))_(u)O(CR³R^(3a))_(w), (CR³R^(3a))_(u)NR³(CR³R^(3a))_(w),    (CR³R^(3a))_(u)C(O) NR³ (CR³R^(3a))_(w), (CR³R^(3a))_(u) NR³C(O)    (CR³R^(3a))_(w), (CR³R^(3a))_(u)OC(O)NR³(CR³R^(3a))_(w),    (CR³R^(3a))_(u)NR³C(O)O(CR³R^(3a))_(w),    (CR³R^(3a))_(u)NR³C(O)NR³(CR³R^(3a))_(w),    (CR³R^(3a))_(u)NR³C(S)NR³(CR³R^(3a))_(w),    (CR³R^(3a))_(u)S(CR³R^(3a))_(w), (CR³R^(3a))_(u)S(O)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)S(O)₂(CR³R^(3a))_(w),    (CR³R^(3a))_(u)S(O)NR³(CR³R^(3a))_(w),    (CR³R^(3a))_(u)NR³S(O)₂(CR³R^(3a))_(w),    (CR³R^(3a))_(u)S(O)₂NR³(CR³R^(3a))_(w), and    (CR³R^(3a))_(u)NR³S(O)₂NR³(CR³R^(3a))_(w), wherein u+w total 0, 1,    2, 3, or 4, provided that G₁ does not form a N—N, N—O, N—S, NCH₂N,    NCH₂O, or NCH₂S bond with either group to which it is attached;-   X is selected from —(CR²R^(2a))₁₋₄—, —CR²(CR²R^(2b))(CH₂)_(t)—,    —C(O)—, —C(═NR^(1c))—, —CR²(NR^(1c)R²)—, —CR²(OR²)—, —CR²(SR²)—,    —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —S—, —S(O)—, —S(O)₂—, —SCR²R^(2a)—,    —S(O)CR²R^(2a)—, —(O)₂CR²R^(2a)—, —CR²R^(2a)S—, —CR²R^(2a)S(O)—,    —CR²R^(2a)S(O)₂—, —S(O)₂NR²—, —NR²S(O)₂—, —NR²S(O)₂CR²R^(2a)—,    —CR²R^(2a)S(O)₂NR²—, —NR²S(O)₂NR²—, —C(O)NR²—, —NR²C(O)—,    —C(O)NR²CR²R^(2a)—, —NR²C(O)₂CR²R^(2a)—, —CR²R^(2a)C(O)NR²—,    —CR²R^(2a)NR²C(O)—, —NR²C(O)O—, —OC(O)NR²—, —NR²C(O)NR²—, —NR²—,    —NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, —CR²R^(2a)O—, and —OCR²R^(2a)—;-   Y is selected from:

C₃₋₁₀ carbocycle substituted with 0-2 R^(4a), and,

5-10 membered heterocycle consisting of: carbon atoms and 1-4heteroatoms selected from the group consisting of N, O, and S(O)_(p)substituted with 0-2 R^(4a);

-   Z is selected from —(CR²R^(2a))₁₋₄—, (CR²R^(2a))_(q)O    (CR²R^(2a))_(q1), (CR²R^(2a))_(q)NR³(CR²R^(2a))_(q1),    (CR²R^(2a))_(q)C(O)(CR²R^(2a))_(q1),    (CR²R^(2a))_(q)C(O)O(CR²R^(2a))_(q1),    (CR²R^(2a))_(q)OC(O)(CR²R^(2a))_(q1),    (CR²R^(2a))_(q)C(O)NR³(CR²R^(2a))_(q1),    (CH₂)_(q)NR³C(O)(CR²R^(2a))_(q1),    (CR²R^(2a))_(q)OC(O)O(CR²R^(2a))_(q1),    (CH₂)_(q)OC(O)NR³(CR²R^(2a))_(q1),    (CR²R^(2a))_(q)NR³C(O)O(CR²R^(2a))_(q1),    (CH₂)_(q)NR³C(O)NR³(CR²R^(2a))_(q1),    (CR²R^(2a))_(q)S(CR²R^(2a))_(q1),    (CR²R^(2a))_(q)S(O)(CR²R^(2a))_(q1), (CH₂)_(q)S(O)₂(CR²R^(2a))_(q1),    (CR²R^(2a))_(q)SO₂NR³(CR²R^(2a))_(q1),    (CH₂)_(q)NR³SO₂(CR²R^(2a))_(q1), and    (CR²R^(2a))_(q)NR³SO₂NR³(CR²R^(2a))_(q1), wherein q+q1 total 0, 1,    or 2, provided that Z does not form a N—N, N—O, N—S, NCH₂N, NCH₂O,    or NCH₂S bond with either group to which it is attached;-   Z² is selected from H, C₁₋₄ alkyl, phenyl, benzyl, C(O)R³, and    S(O)_(p)R^(3c);-   R^(1a) is selected from H, —(CH₂)_(r)—R^(1b), —CH═CH—R^(1b),    NCH₂R^(1c), OCH₂R^(1c), SCH₂R^(1c), NH(CH₂)₂(CH₂)_(t)R^(1b),    O(CH₂)₂(CH₂)_(t)R^(1b), S(CH₂)₂(CH₂)_(t)R^(1b),    S(O)_(p)(CH₂)_(r)R^(1d), O(CH₂)_(r)R^(1d), NR³(CH₂)_(r)R^(1d),    OC(O)NR³(CH₂)_(r)R^(1d), NR³C(O)NR³(CH₂)_(r)R^(1d),    NR³C(O)O(CH₂)_(r)R^(1d), and NR³C(O)(CH₂)_(r)R^(1d), provided that    R^(1a) forms other than an N-halo, N—N, N—S, N—O, or N—CN bond;-   alternatively, when two R^(1a)'s are attached to adjacent atoms,    together with the atoms to which they are attached, they form a 5-7    membered ring consisting of: carbon atoms and 0-2 heteroatoms    selected from the group consisting of N, O, and S(O)_(p), this ring    being substituted with 0-2 R^(4b) and comprising: 0-3 double bonds;-   R^(1b) is selected from H, C₁₋₃ alkyl, F, Cl, Br, I, —CN, —CHO,    (CF₂)_(r)CF₃, (CH₂)_(r)OR², NR²R^(2a), C(O)R^(2c), OC(O)R²,    (CF₂)_(r)CO₂R^(2a), S(O)_(p)R^(2b), NR²(CH₂)_(r)OR²,    C(═NR²C)NR²R^(2a), NR²C(O)R^(2b), NR²C(O)NHR^(2b), NR²C(O)₂R^(2a),    OC(O)NR^(2a)R^(2b), C(O)NR²R^(2a), C(O)NR²(CH₂)_(r)OR²,    SO₂NR²R^(2a), NR²SO₂R^(2b), C₃₋₆ carbocycle substituted with 0-2    R^(4a), and 5-10 membered heterocycle consisting of carbon atoms and    from 1-4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p) substituted with 0-2 R^(4a), provided that R^(1b) forms    other than an N-halo, N—N, N—S, N—O, or N—CN bond;-   R^(1c) is selected from H, CH(CH₂OR²)₂, C(O)R^(2c), C(O)NR²R^(2a),    S(O)R^(2b), S(O)₂R^(2b), and SO₂NR²R^(2a);-   R^(1d) is selected from C₃₋₆ carbocycle substituted with 0-2 R^(4a)    and 5-10 membered heterocycle consisting of carbon atoms and from    1-4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p) substituted with 0-2 R^(4a), provided that R^(id) forms    other than an N—N, N—S, or N—O bond;-   R², at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl,    C₃₋₆ carbocycle substituted with 0-2 R^(4b), a C₃₋₆ carbocycle-CH₂—    substituted with 0-2 R^(4b), and 5-6 membered heterocycle consisting    of: carbon atoms and 1-4 heteroatoms selected from the group    consisting of N, O, and S(O)_(p) substituted with 0-2 R^(4b);-   R^(2a), at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl,    benzyl, C₃₋₆ carbocycle substituted with 0-2 R^(4b), and 5-6    membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p) substituted    with 0-2 R^(4b);-   R^(2b), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy, C₁₋₆    alkyl, benzyl, C₃₋₆ carbocycle substituted with 0-2 R^(4b), and 5-6    membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p) substituted    with 0-2 R^(4b);-   R^(2c), at each occurrence, is selected from CF₃, OH, C₁₋₄ alkoxy,    C₁₋₆ alkyl, benzyl, C₃₋₆ carbocycle substituted with 0-2 R^(4b), and    5-6 membered heterocyclic system containing from 1-4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p) substituted    with 0-2 R^(4b);-   alternatively, R² and R^(2a), together with the atom to which they    are attached, combine to form a 5 or 6 membered saturated, partially    saturated or unsaturated ring substituted with 0-2 R^(4b) and    consisting of: 0-1 additional heteroatoms selected from the group    consisting of N, O, and S(O)_(p);-   R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;-   R^(3a), at each occurrence, is selected from H, C₁₋₄ alkyl, benzyl,    and phenyl;-   R^(3b), at each occurrence, is selected from H, C₁₋₄ alkyl, and    phenyl;-   R^(3c), at each occurrence, is selected from C₁₋₄ alkyl, benzyl, and    phenyl;-   R^(3d), at each occurrence, is selected from H, C₁₋₄ alkyl, C₁₋₄    alkyl-phenyl, and C(═O)R^(3c);-   R⁴, at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², F, Cl,    Br, I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a),    (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b), C(O)NR²R^(2a), NR²C(O)NR²R^(2a),    C(═NR²)NR²R^(2a), C(═NS(O)₂R⁵)NR²R^(2a), NHC(═NR²)NR²R^(2a), C(O)NHC    (═NR²)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl,    NR²SO₂R⁵, S(O)_(p)R⁵, (CF₂)_(r)CF₃, NCH₂R^(1c), OCH₂R^(1c),    SCH₂R^(1c), N(CH₂)₂(CH₂)_(t)R^(1b), O(CH₂)₂(CH₂)_(t)R^(1b), and    S(CH₂)₂(CH₂)_(t)R^(1b);-   alternatively, one R⁴ is a 5-6 membered aromatic heterocycle    consisting of: carbon atoms and 1-4 heteroatoms selected from the    group consisting of N, O, and S(O)_(p);-   R^(4a), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR²,    (CH₂)_(r)—F, (CH₂)_(r)—Br, (CH₂)_(r)—Cl, Cl, Br, F, I, C₁₋₄ alkyl,    s-CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b),    C(O)NR²R^(2a), (CH₂)_(r)N═CHOR³, C(O)NH(CH₂)₂NR²R^(2a),    NR²C(O)NR²R^(2a), C(═NR²)NR²R^(2a), NHC(═NR²)NR²R^(2a),    SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, C(O)NHSO₂—C₁₋₄    alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, and (CF₂)_(r)CF₃;-   alternatively, one R^(4a) is phenyl substituted with 0-1 R⁵ or a 5-6    membered aromatic heterocycle consisting of:

carbon atoms and 1-4 heteroatoms selected from the group consisting ofN, O, and S(O)_(p) substituted with 0-1 R⁵;

-   R^(4b), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR³, F,    Cl, Br, I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR³R^(3a),    (CH₂)_(r)C(O)R³, (CH₂)_(r)C(O)OR^(3c), NR³C(O)R^(3a), C(O)NR³R^(3a),    NR³C(O)NR³R^(3a), C(═NR³)NR³R^(3a), NR³C(═NR³)NR³R^(3a),    SO₂NR³R^(3a), NR³SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃,    NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl, S(O)_(p)-phenyl,    and (CF₂)_(r)CF₃;-   R⁵, at each occurrence, is selected from H, C₁₋₆ alkyl, ═O,    (CH₂)_(r)OR³, F, Cl, Br, I, C₁₋₄ alkyl, —CN, NO₂,    (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³, (CH₂)_(r)C(O)OR^(3c),    NR³C(O)R^(3a), C(O)NR³R^(3a), NR³C(O)NR³R^(3a), CH(═NOR^(3d)),    C(═NR³)NR³R^(3a), NR³C(═NR³) NR³R^(3a), SO₂NR³R^(3a),    NR³SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃, NR³SO₂-phenyl,    S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl, S(O)_(p)-phenyl, (CF₂)_(r)CF₃,    phenyl substituted with 0-2 R⁶, naphthyl substituted with 0-2 R⁶,    and benzyl substituted with 0-2 R⁶;-   R⁶, at each occurrence, is selected from H, OH, (CH₂)_(r)OR², halo,    C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r)NR₂R^(2a), (CH₂)_(r)C(O)R^(2b),    NR²C(O)R^(2b), NR²C(O)NR²R^(2a), C(═NH)NH₂, NHC(═NH)NH₂,    SO₂NR²R^(2a), NR²SO₂NR²R^(2a), and NR²SO₂C₁₋₄ alkyl;-   R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆    alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, (CH₂)_(n)-phenyl,    C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄    alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄    alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and    phenyl C₁₋₄ alkoxycarbonyl;-   R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl, and    (CH₂)_(n)-phenyl;-   alternatively, R⁷ and R⁸ combine to form a 5 or 6 membered    saturated, ring which contains from 0-1 additional heteroatoms    selected from the group consisting of N, O, and S(O)_(p);-   R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl, and    (CH₂)_(n)-phenyl;-   n, at each occurrence, is selected from 0, 1, 2, and 3;-   p, at each occurrence, is selected from 0, 1, and 2;-   r, at each occurrence, is selected from 0, 1, 2, 3, 4, 5, and 6;-   t, at each occurrence, is selected from 0, 1, 2, and 3;-   provided that:

(a) when P₄ is -Z-A-B, M₁ is a carbonyl, and G is substituted with anamidino, guanidino, amino-ethylene, or amino-propylene group, any ofwhich may be substituted or cyclized, then G₁ is present or Z is otherthan a bond or alkylene; and

(b) when P₄ is -G₁-G, M1 is a carbonyl, and G₁ is absent or alkylene,then Z is other than a bond or alkylene;

-   alternatively, when    -   (a) B is other than an optionally substituted carbocycle; and,    -   (b) G₁ is (CR³R^(3a))_(u)NR³(CR³R^(3a))_(w) and u+w is 1, 2, 3,        or 4, (CR³R^(3a))_(u)C(O)NR³(CR³R^(3a))_(w), (CR³R^(3a))        NR³C(O)(CR³R^(3a))_(w), (CR³R^(3a))_(u)S(O)NR³(CR³R^(3a))_(w),        (CR³R^(3a))_(u)S(O)₂NR³(CR³R³a)_(w), or        (CR³R^(3a))_(u)NR³S(O)₂(CR³R^(3a))_(w);        -   then Z is other than (CH₂)NR³, NR³(CH₂), (CH₂)NR³(CH₂),            (CH₂)(CH₂)NR³, NR³(CH₂)(CH₂), (CH₂)_(q)C(O)NR³(CH₂)_(q1),            (CH₂)_(q)NR³C(O)(CH₂)_(q1), (CH₂)_(q)SO₂NR³(CH₂)_(q1), or            (CH₂)_(q)NR³SO₂(CH₂)_(q1);-   alternatively, when    -   (a) B is other than an optionally substituted carbocycle; and,    -   (b) Z is (CH₂)NR³, NR³(CH₂), (CH₂)NR³(CH₂), (CH₂)(CH₂)NR³,        NR³(CH₂)(CH₂), (CH₂)_(q)C(O)NR³(CH₂)_(q1),        (CH₂)_(q)NR³C(O)(CH₂)_(q1), (CH₂)_(q)SO₂NR³(CH₂)_(q1), or        (CH₂)_(q)NR³SO₂(CH₂)_(q1);        -   then G₁ is other than (CR³R^(3a))_(u)NR³(CR³R^(3a))_(w) and            u+w is 1, 2, 3, or 4, (CR³R^(3a))_(u)C(O)            NR³(CR³R^(3a))_(w), (CR³R^(3a))_(u)NR³C(O)(CR³R^(3a))_(w),            (CR³R^(3a))_(u)S(O)NR³(CR³R^(3a))_(w),            (CR³R^(3a))_(u)S(O)₂NR³(CR³R^(3a))_(w), or            (CR³R^(3a))_(u)NR³S(O)₂(CR³R^(3a))_(w).            [2] In a preferred embodiment, the present invention            provides a novel compound, wherein:-   ring M is substituted with 0-2 R^(1a) and is selected from the    group:-   z² is selected from H, C₁₋₄ alkyl, phenyl, benzyl, C(O)R³, and    S(O)_(p)R^(3c);-   ring P, including P₁, P₂, P₃, and P₄ is selected from group:-   G is selected from the group:-   A is selected from one of the following carbocyclic and heterocyclic    systems which are substituted with 0-2 R⁴;    -   phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl,        morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl,        isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl,        oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl,        1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,        1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,        1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,        1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl,        benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl,        benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and        isoindazolyl;-   B is selected from Y, X—Y, CH₂NR²R^(2a), and CH₂CH₂NR²R^(2a);-   G₁ is absent or is selected from (CR³R^(3a))₁₋₃,    (CR³R^(3a))_(u)C(O)(CR³R^(3a))_(w), (CR³R^(3a))_(u)O(CR³R^(3a))_(w),    (CR³R^(3a))_(u)NR³(CR³CR^(3a))_(w),    (CR³R^(3a))_(u)C(O)NR³(CR³R^(3a))_(w),    (CR³R^(3a))_(u)NR³C(O)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)S(CR³R^(3a))_(w), (CR³R^(3a))_(u)S(O)(CR³R^(3a))_(w),    (CR³R^(3a))_(u)S(O)₂(CR³R^(3a))_(w),    (CR³R^(3a))_(u)S(O)NR³(CR³R^(3a))_(w), and    (CR³R^(3a))_(u)S(O)₂NR³(CR³R^(3a))_(w), wherein u+w total 0, 1, or    2, provided that G₁ does not form a N—N, N—O, N—S, NCH₂N, NCH₂O, or    NCH₂S bond with either group to which it is attached;-   X is selected from —(CR²R^(2a))₁₋₄—, —C(O)—, —C(═NR^(1c))—,    —CR²(NR^(1c)R²)—, —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —C(O)NR²—,    —NR²C(O)—, —C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—,    —CR²R^(2a)C(O)NR²—, —CR²R^(2a)NR²C(O)—, —NR²C(O)NR²—, —NR²—,    —NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, —CR²R^(2a)O—, and —OCR²R^(2a)—;-   Y is selected from one of the following carbocyclic and heterocyclic    systems that are substituted with 0-2 R^(4a);    -   cyclopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl,        piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl,        thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl,        isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl,        1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,        1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,        1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl,        1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl,        benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl,        benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and        isoindazolyl;-   alternatively, Y is selected from the following bicyclic heteroaryl    ring systems:-   K is selected from O, S, NH, and N;-   Z is selected from CH₂O, OCH₂, NH, CH₂NH, NHCH₂, CH₂C(O), C(O)CH₂,    C(O)NH, NHC(O), CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and NHSO₂, provided    that Z does not form a N—N, N—O, N—S, NCH₂N, NCH₂O, or NCH₂S bond    with either group to which it is attached;-   alternatively, when    -   (a) B is other than an optionally substituted carbocycle; and,    -   (b) G₁ is (CH₂)_(u)NR³(CH₂)_(w) and u+w is 1 or 2,        (CH₂)_(u)C(O)NR³(CH₂)_(w), (CH₂)_(u)NR³C(O)(CH₂)_(w),        (CH₂)_(u)S(O)NR³(CH₂)_(w), (CH₂)_(u)S(O)₂NR³(CH₂)_(w), or        (CH₂)_(u)NR³S(O)₂(CH₂)_(w),;        -   then Z is other than CH₂NH, NHCH₂, C(O)NH, NHC(O), CH₂S(O)₂,            S(O)₂(CH₂), SO₂NH, and NHSO₂;-   alternatively, when    -   (a) B is other than an optionally substituted carbocycle; and,    -   (b) Z is, CH₂NH, NHCH₂, C(O)NH, NHC(O), CH₂S(O)₂, S(O)₂(CH₂),        SO₂NH, and NHSO₂;        -   then G₁ is other than (CR³R^(3a))_(u)NR³(CH₂)_(w) and u+w is            1, 2, 3, or 4, (CH₂)^(u)C(O)NR³(CH₂)_(w),            (CR³R^(3a))_(u)NR³C(O)(CH₂)_(w), (CH₂)_(u)S(O)NR³(CH₂)_(w),            (CR³R^(3a))_(u)S(O)₂NR³(CH₂)_(w), or            (CH₂)_(u)NR³S(O)₂(CH₂)_(w).            [3] In another preferred embodiment, the present invention            provides a novel compound, wherein:-   ring M is substituted with 0-2 R^(1a) and is selected from the    group:-   ring P, including P₁, P₂, P₃, and P₄ is selected from group:-   G is selected from the group:-   G₁ is absent or is selected from CH₂, CH₂CH₂, CH₂O, OCH₂, NH, CH₂NH,    NHCH₂, CH₂C(O), C(O)CH₂, C(O)NH, NHC(O), CH₂S(O)₂, S(O)₂(CH₂),    SO₂NH, and NHSO₂, provided that G₁ does not form a N—N, N—O, N—S,    NCH₂N, NCH₂O, or NCH₂S bond with either group to which it is    attached;-   Z is selected from CH₂O, OCH₂, NH, CH₂NH, NHCH₂, CH₂C(O), C(O)CH₂,    C(O)NH, NHC(O), CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and NHSO₂, provided    that Z does not form a N—N, N—O, N—S, NCH₂N, NCH₂O, or NCH₂S bond    with either group to which it is attached;-   alternatively, when    -   (a) B is other than an optionally substituted carbocycle; and,    -   (b) G₁ is CH₂NH, NHCH₂, C(O)NH, NHC(O), CH₂S(O)₂, S(O)₂(CH₂),        SO₂NH, and NHSO₂;        -   then Z is other than CH₂NH, NHCH₂, C(O)NH, NHC(O), CH₂S(O)₂,            S(O)₂(CH₂), SO₂NH, and NHSO₂;-   alternatively, when    -   (a) B is other than an optionally substituted carbocycle; and,    -   (b) Z is CH₂NH, NHCH₂, C(O)NH, NHC(O), CH₂S(O)₂, S(O)₂(CH₂),        SO₂NH, and NHSO₂;        -   then G₁ is other than CH₂NH, NHCH₂, C(O)NH, NHC(O),            CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and NHSO₂.            [4] In another preferred embodiment, the present invention            provides a novel compound, wherein:-   ring M is substituted with 0-1 R^(1a) and is selected from the    group:-   G is selected from:-   G₁ is absent.    [5] In another preferred embodiment, the present invention provides    a novel compound, wherein;-   ring M is substituted with 0-1 R^(1a) and is selected from the    group:-   ring P, including P1, P2, P₃, and P₄ is selected from group:-   A is selected from phenyl, pyridyl, and pyrimidyl, and is    substituted with 0-2 R⁴;-   B is selected from phenyl, pyrrolidino, N-pyrrolidino-carbonyl,    morpholino, N-morpholino-carbonyl, 1,2,3-triazolyl, imidazolyl, and    benzimidazolyl, and is substituted with 0-1 R^(4a);-   R², at each occurrence, is selected from H, CH₃, CH₂CH₃,    cyclopropylmethyl, cyclobutyl, and cyclopentyl;-   R^(2a), at each occurrence, is H or CH₃;-   alternatively, R² and R^(2a), together with the atom to which they    are attached, combine to form pyrrolidine substituted with 0-2    R^(4b) or piperidine substituted with 0-2 R^(4b);-   R⁴, at each occurrence, is selected from OH, (CH₂)_(r)OR², halo,    C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), and (CF₂)_(r)CF₃;-   R^(4a) is selected from C₁₋₄ alkyl, CF₃, (CH₂)_(r)OR²,    (CH₂)_(r)NR²R^(2a), S(O)_(p)R⁵, SO₂NR²R^(2a), and    1-CF₃-tetrazol-2-yl;-   R^(4b), at each occurrence, is selected from H, CH₃, and OH;-   R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl,    and benzyl; and,-   r, at each occurrence, is selected from 0, 1, and 2.    [6] In another preferred embodiment, the present invention provides    a novel compound, wherein;-   A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl,    2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl,    2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and,-   B is selected from the group: 2-(aminosulfonyl)phenyl,    2-(methylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl,    2-(methylsulfonyl)phenyl, 2-(N,N-dimethylaminomethyl)phenyl,    2-(N-methylaminomethyl)phenyl,    2-(N-ethyl-N-methylaminomethyl)phenyl,    2-(N-pyrrolidinylmethyl)phenyl, 1-methyl-2-imidazolyl,    2-methyl-1-imidazolyl, 2-(dimethylaminomethyl)-1-imidazolyl,    2-(methylaminomethyl)-1-imidazolyl,    2-(N-(cyclopropylmethyl)aminomethyl)phenyl,    2-(N-(cyclobutyl)aminomethyl)phenyl,    2-(N-(cyclopentyl)aminomethyl)phenyl,    2-(N-(4-hydroxypiperidinyl)methyl)phenyl, and    2-(N-(3-hydroxypyrrolidinyl)methyl)phenyl.    [7] In another preferred embodiment, the present invention provides    a novel compound selected from:-   6-(3-(amidino)phenyl)-1-{2′-[aminosulfonyl]-1,1′-biphenyl-4-yl}-3-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;-   N-[1-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6yl]phenyl}-1H-imidazol-2-yl)methyl]-N,N-dimethylamine;-   (3S)—N-[1-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6yl]-1,1′-biphenyl-2yl}methyl-3-pyrrolidinol;    and,-   7-{2′-[(4-hydroxy-1-piperidinyl)methyl]-1,1′-biphenyl-4-yl}-1-(4-methoxyphenyl)-3-(trifluoromethyl)-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one;-   or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides novelpharmaceutical compositions, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of thepresent invention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method fortreating a thromboembolic disorder, comprising: administering to apatient in need thereof a therapeutically effective amount of a compoundof the present invention or a pharmaceutically acceptable salt formthereof.

In another embodiment, the thromboembolic disorder is selected from thegroup consisting of arterial cardiovascular thromboembolic disorders,venous cardiovascular thromboembolic disorders, arterial cerebrovascularthromboembolic disorders, and venous cerebrovascular thromboembolicdisorders.

In another embodiment, the thromboembolic disorder is selected unstableangina, first myocardial infarction, recurrent myocardial infarction,ischemic sudden death, transient ischemic attack, stroke,atherosclerosis, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from (a) prosthetic valvesor other implants, (b) indwelling catheters, (c) stents, (d)cardiopulmonary bypass, (e) hemodialysis, and (f) other procedures inwhich blood is exposed to an artificial surface that promotesthrombosis.

In another embodiment, the present invention provides a novel method oftreating a patient in need of thromboembolic disorder treatment,comprising: administering a compound of the present invention or apharmaceutically acceptable salt form thereof in an amount effective totreat a thromboembolic disorder

In another embodiment, the present invention provides a novel method,comprising: administering a compound of the present invention or apharmaceutically acceptable salt form thereof in an amount effective totreat a thromboembolic disorder.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy.

In another embodiment, the present invention provides the use of acompound of the present invention as described above for the manufactureof a medicament for the treatment of a thromboembolic disorder.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional more preferredembodiments. It is also to be understood that each individual element ofthe preferred embodiments is its own independent preferred embodiment.Furthermore, any element of an embodiment is meant to be combined withany and all other elements from any embodiment to describe an additionalembodiment.

Definitions

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated. Allprocesses used to prepare compounds of the present invention andintermediates made therein are considered to be part of the presentinvention. Tautomers of compounds shown or described herein areconsidered to be part of the present invention.

Preferably, the molecular weight of compounds of the present inventionis less than about 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or1000 grams per mole. More preferably, the molecular weight is less thanabout 950 grams per mole. Even more preferably, the molecular weight isless than about 850 grams per mole. Still more preferably, the molecularweight is less than about 750 grams per mole.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced. Keto substituents are not present on aromatic moieties.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium. Isotopes of carbon include C-13 and C-14.

The present invention is also intended to include all stable oxides ofthiol and amino groups, even when not specifically written. When anamino group is listed as a substituent, the N-oxide derivative of theamino group is also included as a substituent. When a thiol group ispresent, the S-oxide and S,S-dioxide derivatives are also included.

When any variable (e.g., R⁶) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R⁶, then saidgroup may optionally be substituted with up to two R⁶ groups and R⁶ ateach occurrence is selected independently from the definition of R⁶.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. C₁₋₁₀ alkyl, is intended to includeC₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups. Examples ofalkyl include, but are not limited to, methyl, ethyl, n-propyl,i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. “Haloalkyl”is intended to include both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbonatoms, substituted with 1 or more halogen (for example —C_(v)F_(w) wherev=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are notlimited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, andpentachloroethyl. “Alkoxy” represents an alkyl group as defined abovewith the indicated number of carbon atoms attached through an oxygenbridge. C₁₋₁₀ alkoxy, is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇,C₈, C₉, and C₁₀ alkoxy groups. Examples of alkoxy include, but are notlimited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy,t-butoxy, n-pentoxy, and s-pentoxy. “Cycloalkyl” is intended to includesaturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl.C₃₋₇ cycloalkyl is intended to include C₃, C₄, C₅, C₆, and C₇ cycloalkylgroups. Alkenyl” is intended to include hydrocarbon chains of eitherstraight or branched configuration and one or more unsaturatedcarbon-carbon bonds that may occur in any stable point along the chain,such as ethenyl and propenyl. C₂₋₁₀ alkenyl is intended to include C₂,C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkenyl groups. “Alkynyl” isintended to include hydrocarbon chains of either straight or branchedconfiguration and one or more triple carbon-carbon bonds that may occurin any stable point along the chain, such as ethynyl and propynyl. C₂₋₁₀Alkynyl is intended to include C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀alkynyl groups.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, and sulfate.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7,8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which maybe saturated, partially unsaturated, or aromatic. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane,[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl,and tetrahydronaphthyl.

As used herein, the term “heterocycle” or “heterocyclic system” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated,partially unsaturated or unsaturated (aromatic), and which consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O, and S and including any bicyclic group inwhich any of the above-defined heterocyclic rings is fused to a benzenering. The nitrogen and sulfur heteroatoms may optionally be oxidized.The nitrogen atom may be substituted or unsubstituted (i.e., N or NRwherein R is H or another substituent, if defined). The heterocyclicring may be attached to its pendant group at any heteroatom or carbonatom that results in a stable structure. The heterocyclic ringsdescribed herein may be substituted on carbon or on a nitrogen atom ifthe resulting compound is stable. A nitrogen in the heterocycle mayoptionally be quaternized. It is preferred that when the total number ofS and O atoms in the heterocycle exceeds 1, then these heteroatoms arenot adjacent to one another. It is preferred that the total number of Sand O atoms in the heterocycle is not more than 1. As used herein, theterm “aromatic heterocyclic system” or “heteroaryl” is intended to meana stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or10-membered bicyclic heterocyclic aromatic ring which consists of carbonatoms and 1, 2, 3, or 4 heteroatoms independently selected from thegroup consisting of N, O, and S. It is to be noted that total number ofS and O atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl. Also included are fused ring and spiro compounds containing,for example, the above heterocycles.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic toxic inorganic or organic acids. Forexample, such conventional non-toxic salts include those derived frominorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,phosphoric, nitric and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.)the compounds of the present invention may be delivered in prodrug form.Thus, the present invention is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are intended to include anycovalently bonded carriers that release an active parent drug of thepresent invention in vivo when such prodrug is administered to amammalian subject. Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, it cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate and benzoate derivatives of alcoholand amine functional groups in the compounds of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Substituted” is intended to indicate that one or more hydrogens on theatom indicated in the expression using “substituted” is replaced with aselection from the indicated group(s), provided that the indicatedatom's normal valency is not exceeded, and that the substitution resultsin a stable compound. When a substituent is keto (i.e., ═O) group, then2 hydrogens on the atom are replaced.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention or an amount of the combination ofcompounds claimed effective to inhibit factor Xa. The combination ofcompounds is preferably a synergistic combination. Synergy, asdescribed, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984,22:27-55, occurs when the effect (in this case, inhibition of factor Xa)of the compounds when administered in combination is greater than theadditive effect of the compounds when administered alone as a singleagent. In general, a synergistic effect is most clearly demonstrated atsub-optimal concentrations of the compounds. Synergy can be in terms oflower cytotoxicity, increased antiviral effect, or some other beneficialeffect of the combination compared with the individual components.

Synthesis

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. It will be understood by those skilledin the art of organic synthesis that the functionality present on themolecule should be consistent with the transformations proposed. Thiswill sometimes require a judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention. It will also berecognized that another major consideration in the planning of anysynthetic route in this field is the judicious choice of the protectinggroup used for protection of the reactive functional groups present inthe compounds described in this invention. An authoritative accountdescribing the many alternatives to the trained practitioner is Greeneand Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).All references cited herein are hereby incorporated in their entiretyherein by reference.

The pyridone or cycloheptanone moieties of the present invention aregenerally constructed according to the method outlined in Scheme-1.

Pyridone compound 1 can be treated with PCl₅ to afford the correspondingdihalo intermediate 3, which on refluxing with morpholine should provideenamine 4 (Scheme-2).

Morpholine enamine 4 can be converted to the diketo cyclic amidecompound 5 by treatment with an appropriate acid chloride or anhydridefollowed by acid hydrolysis. Alternatively, enamine 4 can be subjectedto a [3+2] cycloaddition (Scheme-3) with an appropriate nitrile oxide toafford the cyloadduct that on treatment with acid affords thecorresponding isoxazole. The isoxazole can be reduced using conventionaltechniques known in the art to afford a diverse set of diketo cyclicintermediates such as 5. Condensation of 5 with an appropriate hydrazoneshould afford pyrazoline intermediates, which on treatment with acidshould afford the desired pyrazole compounds of the present invention.Reduction of the amide carbonyl with borane should also afford thepyrazolopiperidyl intermediates as shown in scheme-3.

In the case when R₁ is a substituted haloaryl or a substitutedhalo-heteroaryl, the intermediate can be subjected to cross-couplingSuzuki reactions to afford biaryl or heteroaryl derivatives (Scheme-4).Alternatively similar results can be obtained using Stille tin-palladiumcoupling procedures. Depending on the type of boronic acid employed,various compounds of this invention can be obtained. Alternatively, thehalo precursors can be subjected to Ullman copper coupling procedures toafford various nitrogen heterocycles (such as Example 9). This can befurther reduced to afford compounds of this invention such as thepyrazolopiperidyl analog shown in scheme-4.

In the case where R¹ is a proton in intermediate 7, it can be coupled tovarious isocyanates or sulfonyl chlorides to afford the correspondingureas or sulfonamide derivatives (Scheme-5). Alkylation can also affordthe desired alkyl derivatives. The corresponding halo intermediates canbe subjected to Suzuki or Ullman coupling procedures describedpreviously to obtain compounds of the present invention.

It should be noted that the cyano functionality can be converted tobenzamidine, benzamidine, hydroxyamidine, and amidinocarbamoyl speciesby the method shown in Scheme-6. Other compounds of this inventionlacking the camido carbonyl can be directly btained by the reduction ofthe pyrazole intermediate 7 as previously discussed. Following theprocedures in scheme-5 other compounds of this invention ca be obtained.

Other cyano precursors can be converted to various compounds of thepresent invention as illustrated in Scheme-7.

Other pyrazole compounds of the present invention can be prepared viamethods illustrated in Scheme-8.

It should be noted that pyrazolo-cycloheptyl-amido analogs such as thatillustrated in Scheme-1 could also be subjected to the methods describedabove to obtain compounds of the present invention.

Pyrazoles (or other 5-membered heterocycles) of this invention whereinboth G₁ and Z are present can be easily obtained via intermediates shownin schemes 1-7.

-   Alternatively they can be prepared via the methodology outlined in    scheme-9. Those who are skilled in the art can easily accomplish    elaborations of these to compounds of this invention.

Triazoles of the present invention can be prepared via [3+2]cycloaddition of the morpholine enamine intermediate from scheme-2 withan appropriate azido precursor shown in scheme-10. Elimination of themorpholino itermediate should afford key intermediates that can then betransformed to compounds of the present invention via the methodspreviously shown.

Various other triazoles can be prepared via the methods employed for thepyrazole analogs. Imidazole analogs can also be prepared from themorpholine enamine intermediate shown in Scheme-11.

Imidazole precursor analogs can also be converted to the compounds ofthe present invention via the methods previously described.

Alternatively, pyrazole, imidazole, and triazole carboxylates can alsoserve as versatile intermediates towards the synthesis of other analogsof this invention. For example, N-1 phenyl pyrazole 5-carboxlates can benitrated at the 4-position to the corresponding nitro analog(Scheme-12). Reduction of the nitro to the amino can be accomplishedquite readily. The 4-amino-5-carboxylate can be converted to anappropriate amino-amido species that then can be cyclized to variousaza-bicyclics via methods known to those in the art.

In a similar way triazole and imidazole analogs can be prepared(Scheme-13).

The above aza analogs can then be converted to the compounds of thepresent invention via methods previously described.

Des-carbonyl compounds of the present invention can be prepared via themethodologies outlined in Schemes 14-17.

Other compounds of this invention can be obtained via the methodologyoutlined in Scheme-18

The isoxazole analogs of this invention can also be converted to thepyrazole analogs via the method described in Scheme-19.

Furan analogs can also be obtained via the methodology of Bourzat et.al. (Bull. Chem. Soc. Fr. 1971, 1727) according to Scheme-20. Thiopheneand pyrrole analogs can similarly be prepared. Compounds of thisinvention can be obtained by further elaborations of these intermediatesas previously described for similar analogs.

Scheme 21 describes additional N-Pyrazole derivatives that can beobtained via the above-described methodologies.

Scheme 22 describes how benzisoxazines can be prepared. Benzisothiazinescould be prepared in a similar manner.

The A-B moieties can be prepared by methods known to those of skill inthe art. The following publications, the contents of which areincorporated herein by reference, describe and exemplify means ofpreparing A-B moieties: WO97/23212, WO97/30971, WO97/38984, WO98/06694,WO98/01428, WO98/28269, WO98/28282, WO99/12903, WO98/57934, WO98/57937,WO98/57951, WO99/32454, WO99/50255, WO00/39131, WO00/38683, WO00/39102,WO01/05784, and WO00/39108.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES Example 16-(3-(amidino)phenyl)-1-{2′-[aminosulfonyl]-1,1′-biphenyl-4-yl}-3-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine

Part-A. To a DMF (50 mL) solution of 3-cyanoaniline (14.00 g, 33.88 mmol) was added sodium hydride (60% in oil, 1.36 g, 33.88 m mol). Thereaction mixture was allowed to stir at room temperature for 1 hfollowed by the addition of 5-chloro-2-pentanone-ethylene-ketal (5.58 g,33.88 m mol). The combined mixture was refluxed for 72 h. Quenched thereaction mixture with water (300 mL) and the organics were extractedwith ethyl acetate (2×100 mL) dried and evaporated to a brown mass.Chromatography on silica gel (hexane/ethylacetate, 7:3) afforded 0.89 gof an inseparable mixture of mono and di-alkylated products. The mixturewas dissolved in dichloromethane (50 mL) and to this was addedtriethylamine (1 mL) followed by an equivalent of ethyl oxalyl chloride.The reaction was stirred at room temperature for 18 h and then quenchedwith dilute hydrochloric acid (3N, 100 mL). The organics were extractedwith ethyl acetate (2×100 mL) dried with magnesium sulfate andevaporated to afford 0.5 g of the desired acylated product. LRMS 347(M+H).Part-B. The product obtained in part-A was dissolved in dichloromethane(100 mL) and to this solution was added 3N HCL (100 mL). The mixture wasstirred at room temperature for 8 h. The organics were separated, driedand evaporated to afford pure ketone compound 0.39 g. LRMS 302.Part-C. The ketone compound from part-B was dissolved in absoluteethanol (20 mL). To this solution was added 1 equivalent of sodiumethoxide (25% in ethanol). The reaction mixture was stirred at roomtemperature for 3 h. Quenched the reaction with dilute hydrochloric acid(1N, 100 mL). The organics were extracted with ethyl acetate (2×50 mL),dried and evaporated to afford a pale yellow mass (0.35 g). ¹H NMR(CDCl₃) δ: 6.60(m, 2H), 7.58(m, 2H), 3.88(t, 2H0, 2.81(t, 2H), 2.45(s,3H)ppm. LRMS 257(M+H).Part-D. The diketo-piperidone intermediate obtained in part-C (0.19 g,0.75 m mol) was dissolved in absolute methanol (20 mL). To this wasadded 4-bromophenylhydrazine (0.17 g, 0.75 m mol) and the reaction wasallowed to reflux overnight. Methanol was evaporated and the product wasdirectly subjected to purification via silica gel column chromatography(hexane/ethylacetate, 7:3) to afford 0.25 g of pure pyrazoleintermediate. ¹H NMR (CDCl₃) δ: 7.40-7.65(m, 8H), 4.05(t, 2H), 2.92(t,2H), 2.35(s, 3H) ppm. LRMS 409 (M+H).Part-E. The pyrazole of part-D (0.070 g, 0.21 m mol) was dissolved in asolution of ethanol:toluene (1:1, 20 mL). To this was addedortho-t-butylsulfonamide-phenylboronic acid (0.051 g, 0.21 m mol)followed by aqueous sodium carbonate (2M, 0.3 mL) and Pd₄(PPh₃)₄ cat.The reaction was refluxed for 12 h, cooled, and quenched with water (50mL). The organics were extracted with ethylacetate (2×50 mL), dried andevaporated to afford the desired pyrazole biphenylsulfonamide precursor(0.071 g). LRMS 562.5 (M+H). ¹H NMR (CDCl₃) δ: 8.20(d, 1H), 7.30-7.70(m,11H), 4.08(t, 2H0, 3.60(s, 1H0, 2.95(t, 2H), 2.40(s, 3H), 1.01(s,9H)ppm.Part-F. The product from part-E was dissolved in absolute methanol (50mL) and cooled to 0° C. To this cold solution was bubbled HCl gas for 15min. The reaction mixture was stirred at r.t. for 18 h then cooled andre-dissolved in methanol (20 mL). To this solution was added excessammonium carbonate and the mixture was stirred for an additional 18 h.The methanol was evaporated and the residue was quenched with HCl (1N,1mL). The crude material was then purified via reverse phase preparatoryHPLC (gradient, acteonitrile/water). The desired product was obtainedafter lyophilization as a colorless solid. LRMS 501(M+H). HRMS found501.170886.

Example 2N-[1-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6yl]phenyl}-1H-imidazol-2-yl)methyl]-N,N-dimethylamine

Part-A. To a solution of 4-methoxyphenyl hydrazine(1.0 g, 5.73 m mol) inethanol(20 mL) was added acetic acid(10 mL) and trione(2.35 g, 5.73 mmol). The mixture were brought to reflux and stirred at refluxovernight, cooled to room temperature and evaporated. The crude waspartitioned between ethylacetate and water, washed with water, driedover sodium sulfate, filtered and concentrated. Flash chromatographywith 25% ethylacetate in hexane afforded 4-methoxy-pyrazolopyridinoneintermediate (2.6 g). CI mass spectrum m/z (rel. intensity) 514 (M+H,100).Part-B. The above intermediate (256 mg, 0.5 m mol) was. dissolved in THF(10 mL). To the solution was added borane THF complex (1 M solution, 5mL). The reaction was stirred at 50° C. for 48 hours, partitionedbetween ethylacetate and water, washed with 1 N HCl and brine, driedover sodium sulfate, filtered, and concentrated to afford the descarbonyl intermediate (240 mg). CI mass spectrum m/z (rel. intensity)500 (M+H, 100).Part-C. The des carbonyl intermediate (80 mg) was reacted with2-N,N-dimethylaminomethyl imidazole under regular Ullmann condition togive the desired compound A (15 mg). CI mass spectrum m/z (rel.intensity) 497 (M+H, 100). ¹H NMR (CD₃OD): δ=2.77 (s, 6H) ; 2.88 (t, 2H); 3.79 (t, 2H); 3.88 (s, 3H); 4.29 (s, 2H); 4.52 (s, 2H); 7.13 (m; 4H);7.37 (m, 3H); 7.52 (m, 3H).

Example 3(3S)—N-[1-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6yl]-1,1′-biphenyl-2yl}methyl-3-pyrrolidinol

Part-A. To a solution of des carbonyl intermediate (160 mg, obtained inpart B of example 2 in THF (10 mL) was added water (5 mL), sodiumcarbonate(102 mg), 2-formylphenylboronic acid(58 mg), andtetrakis(triphenylphosphine) palladium(0)(19 mg). The mixture weredegassed under argon and stirred at reflux for 3 h. The mixture waspartitioned between ethylacetate and water, washed with water and brine,dried over sodium sulfate, filtered, and concentrated. Flashchromatography with 40% ethylacetate in hexane gave the des carbonylaldehyde intermediate(145 mg). ESI mass spectrum m/z (rel. intensity)478 (M+H, 100).Part-B. The above intermediate (40 mg) was dissolved in methylenechloride (10 mL), (R)-3-hydroxypyrrolidine (15 mg) was added followed byaddition of sodium triacetoxyboron hydrate(15 mg). The reaction wasstirred at room temperature overnight. Evaporation of the solventfollowed by HPLC(RP) purification afforded the title compound (18 mg).ESI mass spectrum m/z (rel. intensity) 549 (M+H, 100).

Example 47-{2′-[(4-hydroxy-1-piperidinyl)methyl]-1,1′-biphenyl-4-yl}-1-(4-methoxyphenyl)-3-(trifluoromethyl)-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one

Ethyl 4-(4-methoxyphenyl)-2-(trifluoromethyl)-1H-imidazole-5-carboxylate

A suspension of ethyl p-methoxybenzoylacetate (16.3 mL, 85 m mol) andSeO₂ (9.9 g, 89 m mol) in 80 mL of dioxane was heated to refluxovernight. After being cooled down to rt, the reaction mixture wasfiltered to remove inorganic solid. The filtrate was concentrated underreduced pressure and treated with benzene. The benzene solution wasconcentrated to dryness under reduced pressure to yield ethyl2,3-dioxo-(p-methoxyphenyl) -propionate, which was used in next stepwithout further purification.

To a slurry of NH₄OAc (50 g, 651 m mol) in 170 mL of acetic acid wasadded the above tricarbonyl compound (15.5 g, 65.1 m mol) followed bytrifluoroacetaldehyde hemiethyl acetal (16.8 mL, 130 m mol). The mixturewas heated to 65° C. and stirred for 3 h. The solution was cooled to rtand the acetic acid was evaporated to give an oily residue. This residuewas dissolved in ethyl acetate and washed with sat. NaHCO₃, water, andbrine. The organic phase was then dried (Na₂SO₄), filtered, andconcentrated. Silica gel chromatography provided the correspondingimidazole compound (10.9 g, 53% in 2 steps). ¹H NMR (CDCl₃): δ 7.58 (2H,d, J=8.8 Hz), 6.85 (2H, d, J=8.8 Hz), 4.08 (2H, q, J=7.3 Hz), 3.78 (3H,s), 1.23 (1H, t, J=7.3 Hz) ppm. ¹⁹F NMR (CDCl3) δ −64.19 ppm. ESI MS:m/z 315 (ES+), 313 (ES⁻)

N-(4-bromophenyl)-N-(2-hydroxyethyl)-4-(4-methoxyphenyl)-2-(trifuoromethyl)-1H-imidazole-5-carboxamide

A mixture of the imidazole ethyl ester (9.27 g, 29.5 m mol) and LiOH(8.0 g) in MeOH—H₂O (150 mL, 2:1) was stirred at rt overnight. Afterremoving most of the MeOH under reduced pressure, the mixture wasneutralized with aq. HCl and extracted with EtOAc. The combined organiclayers were dried over MgSO₄, filtered, concentrated to dry, and useddirectly in next step. ESI MS: m/z 285 (ES⁻).

The imidazole acid (7.6 g, 26.55 m mol) in 100 mL of methylene chloridewas treated with oxalyl chloride (6.98 mL, 79.65 m mol), followed by acatalytic amount of DMF. After stirring overnight at rt, the reactionmixture was concentrated to dry under reduced pressure and exposed tohigh vacuum to provide the corresponding acid chloride.

A mixture of p-bromoaniline (17.2 g, 100 m mol) and bromoethanol (3.54mL, 50 m mol) in a 50 mL round bottle was heated gradually to 70° C. andthen was stirred at 70° C. overnight. The reaction mixture was thencooled, basified with aq. NaOH, and extracted with ether. The etherlayers were dried over Na₂SO₄ and concentrated to near dryness.N-β-hydroxyethyl-p-bromoaniline was obtained as a crystalline material(5.1 g, 47%). ¹H NMR (CDCl₃): δ 7.28 (2H, d, J=8.8 Hz), 6.60 (2H, d,J=8.8 Hz), 3.86 (2H, t, J=5.1 Hz), 3.29 (2H, t, J=5.1 Hz), 3.00 (2H, brs) ppm.

To N-β-hydroxyethyl-p-bromoaniline (5.1 g, 23.6 m mol) in 100 mL ofbenzene was added 200 mL of 1N NaOH, followed by the crude acid chloride(˜23.6 m mol) made above. The resulted mixture was stirred at rt for 1h. The benzene layer was separated. The water layer was extracted withethyl acetate. The combined organic layers were dried over Na₂SO₄,concentrated, and applied to silica gel chromatography to generate theimidazole amide compound (1.71 g, 15% in 3 steps). APCI MS: m/z 484, 486(AP⁺), 482, 484 (AP⁻).

7-(4-bromophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one

To a solution of the imidazole amide (0.78 g, 1.61 m mol) in 20 mL ofmethylene chloride was added PBr₃ (0.46 mL, 4.83 m mol) dropwise. Theresulting reaction mixture was stirred at rt for 30 min, then quenchedat 0° C. with aq. Na₂CO₃ and extracted with methylene chloride. Thecombined organic layers were dried over MgSO₄ and concentrated todryness. The resulting imidazole bromide compound was used directly innext step.

The crude imidazole bromide compound was dissolved in 6 mL of DMF. Tothis solution, sodium hydride (129 mg, 60%, 3.22 m mol) was added at 0°C. under nitrogen atmosphere. The reaction was stirred at rt overnight,then quenched with water at 0° C., and extracted with ethyl acetate. Theextracts were washed with water, brine, dried (Na₂SO₄), and concentratedto dryness. The residue was applied to silica gel chromatography toafford the bicyclic core compound (503 mg, 67% in 2 steps). APCI MS: m/z466, 468 (AP⁺), 464, 466 (AP⁻)

7-{2′-[(4-hydroxy-1-piperidinyl)methyl]-1,1′-biphenyl-4-yl}-1-(4-methoxyphenyl)-3-(trifluoromethyl)-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one

A mixture of the bicyclic bromide (150 mg, 0.322 m mol),2-formylbenzene-boronic acid (58 mg), and K₃PO₄ (226 mg) in 10 mL ofdioxane was degassed with nitrogen for 10 min. To the mixture, Pd(PPh₃)₄(18 mg) was added. The reaction mixture was heated to reflux overnight,under nitrogen. After removal of dioxane under reduced pressure, theresidue was diluted with water and extracted with methylene chloride.The combined organic layers were dried (Na₂SO₄), purified by silica gelchromatography to yield the biphenyl compound (120 mg, 71%). ¹⁹F NMR(CDCL3): δ −60.25 ppm. ESI MS: m/z 492 (ES⁺), 490 (ES⁻).

To a solution of biphenyl aldehyde (10 mg, 0.0203 m mol) in 5 mL ofmethanol, NaBH₄ (1.6 mg, 0.0407 m mol) was added at 0° under nitrogen.The reaction mixture was stirred at rt for 15 min. After quenching withaq. NaHCO₃, the mixture was extracted with methylene chloride, dried(MgSO₄), and concentrated to dryness. The crude material was useddirectly in next step. APCI MS: m/z 494 (AP⁺), 492 (AP⁻).

The crude alcohol made above was treated with PBr₃ (0.006 mL, 0.0407 mmol) at rt for 30 min. The reaction was quenched with aq. NaHCO₃,extracted with methylene chloride, dried, and concentrated to dryness.The crude bromide was used directly in next step.

To a solution of the crude bromide in 5 mL of acetonitrile was addedhydroxypiperidine HCl salt (14 mg, 0.102 m mol) and 0.04 mL of i-Pr₂Net.The reaction mixture was stirred at rt overnight, diluted with water,and extracted with methylene chloride. The extracts were combined, dried(Na₂SO₄), and concentrated to dryness. The residue was dissolved in 4 mLof acetonitrile/water (1:1) mixture, applied to preparative RP-HPLC toafford the title compound as a bis-TFA salt (9.4 mg, 58% in 3 steps). ¹HNMR (CD₃OD): δ 7.71 (5H, m) 7.53 (2H, m), 7.40 (1H, m), 7.32 (2H, d,J.=8.9 Hz), 6.96 (2H, d, J =8.9 Hz), 5.64 (2H, m), 4.79 (2H, m), 4.38(2H, s), 3.79 (3H, s), 3.62 (1H, m), 3.02 (2H, m), 2.71 (2H, m),1.95˜1.60 (4H, m) ppm. ¹⁹F NMR (CD₃OD): δ−62.88, −77.50 ppm. ESI MS: m/z577 (ES⁺).

The following tables contain representative examples of the presentinvention. Each entry in each table is intended to be paired with eachformula at the start of the table. For example, in Tables 1 and 2,example 1 is intended to be paired with each of the formulae.

The following nomenclature is intended for group A in the followingtables.

TABLE 1

-   P₄ is Z-A-B, wherein Z is a bond;-   M3 is -G₁-G, wherein G₁ is a bond;-   G is 4-(methoxy)phenyl;

Ex# A B

-   1. phenyl 2-(NH₂SO₂)phenyl-   2. phenyl 2-(CH₃SO₂)phenyl-   3. phenyl 3-NH₂SO₂₋₄-pyridyl-   4. phenyl 3-CH₃SO₂₋₄-pyridyl-   5. phenyl 2-(CH₃NH)phenyl-   6. phenyl 3-((CH₃)₂NCH₂)-4-pyridyl-   7. phenyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl-   8. phenyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl-   9. phenyl 2-((CH₃)₂NCH₂)phenyl-   10. phenyl 2-((CH₃)NHCH₂)phenyl-   11. phenyl 2-((CH₃CH₂)NHCH₂)phenyl-   12. phenyl 2-((CH₃CH₂)₂NCH₂)phenyl-   13. phenyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl-   14. phenyl 2-(((CH₃)₂CH)NHCH₂)phenyl-   15. phenyl 2-(((CH₃)₂CH)₂NCH₂)phenyl-   16. phenyl 2-((cyclopropyl)NHCH₂)phenyl-   17. phenyl 2-((cyclopropyl)₂NCH₂)phenyl-   18. phenyl 2-((cyclobutyl)NHCH₂)phenyl-   19. phenyl 2-((cyclobutyl)₂NCH₂)phenyl-   20. phenyl 2-((cyclopentyl)NHCH₂)phenyl-   21. phenyl 2-((cyclopentyl)₂NCH₂)phenyl-   22. phenyl 2-((cyclohexyl)NHCH₂)phenyl-   23. phenyl 2-((cyclohexyl)₂NCH₂)phenyl-   24. phenyl 1-CH₃₋₂-imidazolyl-   25. phenyl 2-CH₃₋₁-imidazolyl-   26. phenyl 2-((CH₃)₂NCH₂)-1-imidazolyl-   27. phenyl 2-((CH₃)NHCH₂)-1-imidazolyl-   28. phenyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl-   29. phenyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl-   30. phenyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl-   31. phenyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl-   32. phenyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl-   33. phenyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl-   34. phenyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl-   35. phenyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl-   36. phenyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl-   37. phenyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl-   37. phenyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl-   39. phenyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl-   40. phenyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl-   41. 2-pyridyl 2-(NH₂SO₂)phenyl-   42. 2-pyridyl 2-(CH₃SO₂)phenyl-   43. 2-pyridyl 3-NH₂SO₂₋₄-pyridyl-   44. 2-pyridyl 3-CH₃SO₂₋₄-pyridyl-   45. 2-pyridyl 2-(CH₃NH)phenyl-   46. 2-pyridyl 3-((CH₃)₂NCH₂)-4-pyridyl-   47. 2-pyridyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl-   48. 2-pyridyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl-   49. 2-pyridyl 2-((CH₃)₂NCH₂)phenyl-   50. 2-pyridyl 2-((CH₃)NHCH₂)phenyl-   51. 2-pyridyl 2-((CH₃CH₂)NHCH₂)phenyl-   52. 2-pyridyl 2-((CH₃CH₂)₂NCH₂)phenyl-   53. 2-pyridyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl-   54. 2-pyridyl 2-(((CH₃)₂CH)NHCH₂)phenyl-   55. 2-pyridyl 2-(((CH₃)₂CH)₂NCH₂)phenyl-   56. 2-pyridyl 2-((cyclopropyl)NHCH₂)phenyl-   57. 2-pyridyl 2-((cyclopropyl)₂NCH₂)phenyl-   58. 2-pyridyl 2-((cyclobutyl)NHCH₂)phenyl-   59. 2-pyridyl 2-((cyclobutyl)₂NCH₂)phenyl-   60. 2-pyridyl 2-((cyclopentyl)NHCH₂)phenyl-   61. 2-pyridyl 2-((cyclopentyl)₂NCH₂)phenyl-   62. 2-pyridyl 2-((cyclohexyl)NHCH₂)phenyl-   63. 2-pyridyl 2-((cyclohexyl)₂NCH₂)phenyl-   64. 2-pyridyl 1-CH₃₋₂-imidazolyl-   65. 2-pyridyl 2-CH₃₋₁-imidazolyl-   66. 2-pyridyl 2-((CH₃)₂NCH₂)-1-imidazolyl-   67. 2-pyridyl 2-((CH₃)NHCH₂)-1-imidazolyl-   68. 2-pyridyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl-   69. 2-pyridyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl-   70. 2-pyridyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl-   71. 2-pyridyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl-   72. 2-pyridyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl-   73. 2-pyridyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl-   74. 2-pyridyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl-   75. 2-pyridyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl-   76. 2-pyridyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl-   77. 2-pyridyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl-   78. 2-pyridyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl-   79. 2-pyridyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl-   80. 2-pyridyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl-   81. 3-pyridyl 2-(NH₂SO₂)phenyl-   82. 3-pyridyl 2-(CH₃SO₂)phenyl-   83. 3-pyridyl 3-NH₂SO₂₋₄-pyridyl-   84. 3-pyridyl 3-CH₃SO₂₋₄-pyridyl-   85. 3-pyridyl 2-(CH₃NH)phenyl-   86. 3-pyridyl 3-((CH₃)₂NCH₂)-4-pyridyl-   87. 3-pyridyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl-   88. 3-pyridyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl-   89. 3-pyridyl 2-((CH₃)₂NCH₂)phenyl-   90. 3-pyridyl 2-((CH₃)NHCH₂)phenyl-   91. 3-pyridyl 2-((CH₃CH₂)NHCH₂)phenyl-   92. 3-pyridyl 2-((CH₃CH₂)₂NCH₂)phenyl-   93. 3-pyridyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl-   94. 3-pyridyl 2-(((CH₃)₂CH)NHCH₂)phenyl-   95. 3-pyridyl 2-(((CH₃)₂CH)₂NCH₂)phenyl-   96. 3-pyridyl 2-((cyclopropyl)NHCH₂)phenyl-   97. 3-pyridyl 2-((cyclopropyl)₂NCH₂)phenyl-   98. 3-pyridyl 2-((cyclobutyl)NHCH₂)phenyl-   99. 3-pyridyl 2-((cyclobutyl)₂NCH₂)phenyl-   100. 3-pyridyl 2-((cyclopentyl)NHCH₂)phenyl-   101. 3-pyridyl 2-((cyclopentyl)₂NCH₂)phenyl-   102. 3-pyridyl 2-((cyclohexyl)NHCH₂)phenyl-   103. 3-pyridyl 2-((cyclohexyl)₂NCH₂)phenyl-   104. 3-pyridyl 1-CH₃₋₂-imidazolyl-   105. 3-pyridyl 2-CH₃₋₁-imidazolyl-   106. 3-pyridyl 2-((CH₃)₂NCH₂)-1-imidazolyl-   107. 3-pyridyl 2-((CH₃)NHCH₂)-1-imidazolyl-   108. 3-pyridyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl-   109. 3-pyridyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl-   110. 3-pyridyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl-   111. 3-pyridyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl-   112. 3-pyridyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl-   113. 3-pyridyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl-   114. 3-pyridyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl-   115. 3-pyridyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl-   116. 3-pyridyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl-   117. 3-pyridyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl-   118. 3-pyridyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl-   119. 3-pyridyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl-   120. 3-pyridyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl-   121. 2-pyrimidyl 2-(NH₂SO₂)phenyl-   122. 2-pyrimidyl 2-(CH₃SO₂)phenyl-   123. 2-pyrimidyl 3-NH₂SO₂₋₄-pyridyl-   124. 2-pyrimidyl 3-CH₃SO₂₋₄-pyridyl-   125. 2-pyrimidyl 2-(CH₃NH)phenyl-   126. 2-pyrimidyl 3-((CH₃)₂NCH₂)-4-pyridyl-   127. 2-pyrimidyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl-   128. 2-pyrimidyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl-   129. 2-pyrimidyl 2-((CH₃)₂NCH₂)phenyl-   130. 2-pyrimidyl 2-((CH₃)NHCH₂)phenyl-   131. 2-pyrimidyl 2-((CH₃CH₂)NHCH₂)phenyl-   132. 2-pyrimidyl 2-((CH₃CH₂)₂NCH₂)phenyl-   133. 2-pyrimidyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl-   134. 2-pyrimidyl 2-(((CH₃)₂CH)NHCH₂)phenyl-   135. 2-pyrimidyl 2-(((CH₃)₂CH)₂NCH₂)phenyl-   136. 2-pyrimidyl 2-((cyclopropyl)NHCH₂)phenyl-   137. 2-pyrimidyl 2-((cyclopropyl)₂NCH₂)phenyl-   138. 2-pyrimidyl 2-((cyclobutyl)NHCH₂)phenyl-   139. 2-pyrimidyl 2-((cyclobutyl)₂NCH₂)phenyl-   140. 2-pyrimidyl 2-((cyclopentyl)NHCH₂)phenyl-   141. 2-pyrimidyl 2-((cyclopentyl)₂NCH₂)phenyl-   142. 2-pyrimidyl 2-((cyclohexyl)NHCH₂)phenyl-   143. 2-pyrimidyl 2-((cyclohexyl)₂NCH₂)phenyl-   144. 2-pyrimidyl 1-CH₃₋₂-imidazolyl-   145. 2-pyrimidyl 2-CH₃₋₁-imidazolyl-   146. 2-pyrimidyl 2-((CH₃)₂NCH₂)-1-imidazolyl-   147. 2-pyrimidyl 2-((CH₃)NHCH₂)-1-imidazolyl-   148. 2-pyrimidyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl-   149. 2-pyrimidyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl-   150. 2-pyrimidyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl-   151. 2-pyrimidyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl-   152. 2-pyrimidyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl-   153. 2-pyrimidyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl-   154. 2-pyrimidyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl-   155. 2-pyrimidyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl-   156. 2-pyrimidyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl-   157. 2-pyrimidyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl-   158. 2-pyrimidyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl-   159. 2-pyrimidyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl-   160. 2-pyrimidyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl-   161. 5-pyrimidyl 2-(NH₂SO₂)phenyl-   162. 5-pyrimidyl 2-(CH₃SO₂)phenyl-   163. 5-pyrimidyl 3-NH₂SO₂₋₄-pyridyl-   164. 5-pyrimidyl 3-CH₃SO₂₋₄-pyridyl-   165. 5-pyrimidyl 2-(CH₃NH)phenyl-   166. 5-pyrimidyl 3-((CH₃)₂NCH₂)-4-pyridyl-   167. 5-pyrimidyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl-   168. 5-pyrimidyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl-   169. 5-pyrimidyl 2-((CH₃)₂NCH₂)phenyl-   170. 5-pyrimidyl 2-((CH₃)NHCH₂)phenyl-   171. 5-pyrimidyl 2-((CH₃CH₂)NHCH₂)phenyl-   172. 5-pyrimidyl 2-((CH₃CH₂)₂NCH₂)phenyl-   173. 5-pyrimidyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl-   174. 5-pyrimidyl 2-(((CH₃)₂CH)NHCH₂)phenyl-   175. 5-pyrimidyl 2-(((CH₃)₂CH)₂NCH₂)phenyl-   176. 5-pyrimidyl 2-((cyclopropyl)NHCH₂)phenyl-   177. 5-pyrimidyl 2-((cyclopropyl)₂NCH₂)phenyl-   178. 5-pyrimidyl 2-((cyclobutyl)NHCH₂)phenyl-   179. 5-pyrimidyl 2-((cyclobutyl)₂NCH₂)phenyl-   180. 5-pyrimidyl 2-((cyclopentyl)NHCH₂)phenyl-   181. 5-pyrimidyl 2-((cyclopentyl)₂NCH₂)phenyl-   182. 5-pyrimidyl 2-((cyclohexyl)NHCH₂)phenyl-   183. 5-pyrimidyl 2-((cyclohexyl)₂NCH₂)phenyl-   184. 5-pyrimidyl 1-CH₃₋₂-imidazolyl-   185. 5-pyrimidyl 2-CH₃₋₁-imidazolyl-   186. 5-pyrimidyl 2-((CH₃)₂NCH₂)-1-imidazolyl-   187. 5-pyrimidyl 2-((CH₃)NHCH₂)-1-imidazolyl-   188. 5-pyrimidyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl-   189. 5-pyrimidyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl-   190. 5-pyrimidyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl-   191. 5-pyrimidyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl-   192. 5-pyrimidyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl-   193. 5-pyrimidyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl-   194. 5-pyrimidyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl-   195. 5-pyrimidyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl-   196. 5-pyrimidyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl-   197. 5-pyrimidyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl-   198. 5-pyrimidyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl-   199. 5-pyrimidyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl-   200. 5-pyrimidyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl-   201. 2-C1-phenyl 2-(NH₂SO₂)phenyl-   202. 2-C1-phenyl 2-(CH₃SO₂)phenyl-   203. 2-C1-phenyl 3-NH₂SO₂₋₄-pyridyl-   204. 2-C1-phenyl 3-CH₃SO₂₋₄-pyridyl-   205. 2-C1-phenyl 2-(CH₃NH)phenyl-   206. 2-C1-phenyl 3-((CH₃)₂NCH₂)-4-pyridyl-   207. 2-C1-phenyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl-   208. 2-C1-phenyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl-   209. 2-C1-phenyl 2-((CH₃)₂NCH₂)phenyl-   210. 2-C1-phenyl 2-((CH₃)NHCH₂)phenyl-   211. 2-C1-phenyl 2-(CH₃CH₂)NHCH₂)phenyl-   212. 2-C1-phenyl 2-((CH₃CH₂)₂NCH₂)phenyl-   213. 2-C1-phenyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl-   214. 2-C1-phenyl 2-(((CH₃)₂CH)NHCH₂)phenyl-   215. 2-C1-phenyl 2-(((CH₃)₂CH)₂NCH₂)phenyl-   216. 2-C1-phenyl 2-((cyclopropyl)NHCH₂)phenyl-   217. 2-C1-phenyl 2-((cyclopropyl)₂NCH₂)phenyl-   218. 2-C1-phenyl 2-((cyclobutyl)NHCH₂)phenyl-   219. 2-C1-phenyl 2-((cyclobutyl)₂NCH₂)phenyl-   220. 2-C1-phenyl 2-((cyclopentyl)NHCH₂)phenyl-   221. 2-C1-phenyl 2-((cyclopentyl)₂NCH₂)phenyl-   222. 2-C1-phenyl 2-((cyclohexyl)NHCH₂)phenyl-   223. 2-C1-phenyl 2-((cyclohexyl)₂NCH₂)phenyl-   224. 2-C1-phenyl 1-CH₃₋₂-imidazolyl-   225. 2-C1-phenyl 2-CH₃₋₁-imidazolyl-   226. 2-C1-phenyl 2-((CH₃)₂NCH₂)-1-imidazolyl-   227. 2-C1-phenyl 2-((CH₃)NHCH₂)-1-imidazolyl-   228. 2-C1-phenyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl-   229. 2-C1-phenyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl-   230. 2-C1-phenyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl-   231. 2-C1-phenyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl-   232. 2-C1-phenyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl-   233. 2-C1-phenyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl-   234. 2-C1-phenyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl-   235. 2-C1-phenyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl-   236. 2-C1-phenyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl-   237. 2-C1-phenyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl-   238. 2-C1-phenyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl-   239. 2-C1-phenyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl-   240. 2-C1-phenyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl-   241. 2-F-phenyl 2-(NH₂SO₂)phenyl-   242. 2-F-phenyl 2-(CH₃SO₂)phenyl-   243. 2-F-phenyl 3-NH₂SO₂₋₄-pyridyl-   244. 2-F-phenyl 3-CH₃SO₂₋₄-pyridyl-   245. 2-F-phenyl 2-(CH₃NH)phenyl-   246. 2-F-phenyl 3-((CH₃)₂NCH₂)-4-pyridyl-   247. 2-F-phenyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl-   248. 2-F-phenyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl-   249. 2-F-phenyl 2-((CH₃)₂NCH₂)phenyl-   250. 2-F-phenyl 2-((CH₃)NHCH₂)phenyl-   251. 2-F-phenyl 2-((CH₃CH₂)NHCH₂)phenyl-   252. 2-F-phenyl 2-((CH₃CH₂)₂NCH₂)phenyl-   253. 2-F-phenyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl-   254. 2-F-phenyl 2-(((CH₃)₂CH)NHCH₂)phenyl-   255. 2-F-phenyl 2-(((CH₃)₂CH)₂NCH₂)phenyl-   256. 2-F-phenyl 2-((cyclopropyl)NHCH₂)phenyl-   257. 2-F-phenyl 2-((cyclopropyl)₂NCH₂)phenyl-   258. 2-F-phenyl 2-((cyclobutyl)NHCH₂)phenyl-   259. 2-F-phenyl 2-((cyclobutyl)₂NCH₂)phenyl-   260. 2-F-phenyl 2-((cyclopentyl)NHCH₂)phenyl-   261. 2-F-phenyl 2-((cyclopentyl)₂NCH₂)phenyl-   262. 2-F-phenyl 2-((cyclohexyl)NHCH₂)phenyl-   263. 2-F-phenyl 2-((cyclohexyl)₂NCH₂)phenyl-   264. 2-F-phenyl 1-CH₃₋₂-imidazolyl-   265. 2-F-phenyl 2-CH₃₋₁-imidazolyl-   266. 2-F-phenyl 2-((CH₃)₂NCH₂)-1-imidazolyl-   267. 2-F-phenyl 2-((CH₃)NHCH₂)-1-imidazolyl-   268. 2-F-phenyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl-   269. 2-F-phenyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl-   270. 2-F-phenyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl-   271. 2-F-phenyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl-   272. 2-F-phenyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl-   273. 2-F-phenyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl-   274. 2-F-phenyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl-   275. 2-F-phenyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl-   276. 2-F-phenyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl-   277. 2-F-phenyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl-   278. 2-F-phenyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl-   279. 2-F-phenyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl-   280. 2-F-phenyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl-   281. 2,6-diF-phenyl 2-(NH₂SO₂)phenyl-   282. 2,6-diF-phenyl 2-(CH₃SO₂)phenyl-   283. 2,6-diF-phenyl 3-NH₂SO₂₋₄-pyridyl-   284. 2,6-diF-phenyl 3-CH₃SO₂₋₄-pyridyl-   285. 2,6-diF-phenyl 2-(CH₃NH)phenyl-   286. 2,6-diF-phenyl 3-((CH₃)₂NCH₂)-4-pyridyl-   287. 2,6-diF-phenyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl-   288. 2,6-diF-phenyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl-   289. 2,6-diF-phenyl 2-((CH₃)₂NCH₂)phenyl-   290. 2,6-diF-phenyl 2-((CH₃)NHCH₂)phenyl-   291. 2,6-diF-phenyl 2-((CH₃CH₂)NHCH₂)phenyl-   292. 2,6-diF-phenyl 2-((CH₃CH₂)₂NCH₂)phenyl-   293. 2,6-diF-phenyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl-   294. 2,6-diF-phenyl 2-(((CH₃)₂CH)NHCH₂)phenyl-   295. 2,6-diF-phenyl 2-(((CH₃)₂CH)₂NCH₂)phenyl-   296. 2,6-diF-phenyl 2-((cyclopropyl)NHCH₂)phenyl-   297. 2,6-diF-phenyl 2-((cyclopropyl)₂NCH₂)phenyl-   298. 2,6-diF-phenyl 2-((cyclobutyl)NHCH₂)phenyl-   299. 2,6-diF-phenyl 2-((cyclobutyl)₂NCH₂)phenyl-   300. 2,6-diF-phenyl 2-((cyclopentyl)NHCH₂)phenyl-   301. 2,6-diF-phenyl 2-((cyclopentyl)₂NCH₂)phenyl-   302. 2,6-diF-phenyl 2-((cyclohexyl)NHCH₂)phenyl-   303. 2,6-diF-phenyl 2-((cyclohexyl)₂NCH₂)phenyl-   304. 2,6-diF-phenyl 1-CH₃₋₂-imidazolyl-   305. 2,6-diF-phenyl 2-CH₃₋₁-imidazolyl-   306. 2,6-diF-phenyl 2-((CH₃)₂NCH₂)-1-imidazolyl-   307. 2,6-diF-phenyl 2-((CH₃)NHCH₂)-1-imidazolyl-   308. 2,6-diF-phenyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl-   309. 2,6-diF-phenyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl-   310. 2,6-diF-phenyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl-   311. 2,6-diF-phenyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl-   312. 2,6-diF-phenyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl-   313. 2,6-diF-phenyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl-   314. 2,6-diF-phenyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl-   315. 2,6-diF-phenyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl-   316. 2,6-diF-phenyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl-   317. 2,6-diF-phenyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl-   318. 2,6-diF-phenyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl-   319. 2,6-diF-phenyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl-   320. 2,6-diF-phenyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl-   321. piperidinyl 2-(NH₂SO₂)phenyl-   322. piperidinyl 2-(CH₃SO₂)phenyl-   323. piperidinyl 3-NH₂SO₂₋₄-pyridyl-   324. piperidinyl 3-CH₃SO₂₋₄-pyridyl-   325. piperidinyl 2-(CH₃NH)phenyl-   326. piperidinyl 3-((CH₃)₂NCH₂)-4-pyridyl-   327. piperidinyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl-   328. piperidinyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl-   329. piperidinyl 2-((CH₃)₂NCH₂)phenyl-   330. piperidinyl 2-((CH₃)NHCH₂)phenyl-   331. piperidinyl 2-((CH₃CH₂)NHCH₂)phenyl-   332. piperidinyl 2-((CH₃CH₂)₂NCH₂)phenyl-   333. piperidinyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl-   334. piperidinyl 2-(((CH₃)₂CH)NHCH₂)phenyl-   335. piperidinyl 2-(((CH₃)₂CH)₂NCH₂)phenyl-   336. piperidinyl 2-((cyclopropyl)NHCH₂)phenyl-   337. piperidinyl 2-((cyclopropyl)₂NCH₂)phenyl-   338. piperidinyl 2-((cyclobutyl)NHCH₂)phenyl-   339. piperidinyl 2-((cyclobutyl)₂NCH₂)phenyl-   340. piperidinyl 2-((cyclopentyl)NHCH₂)phenyl-   341. piperidinyl 2-((cyclopentyl)₂NCH₂)phenyl-   342. piperidinyl 2-((cyclohexyl)NHCH₂)phenyl-   343. piperidinyl 2-((cyclohexyl)₂NCH₂)phenyl-   344. piperidinyl 1-CH₃₋₂-imidazolyl-   345. piperidinyl 2-CH₃₋₁-imidazolyl-   346. piperidinyl 2-((CH₃)₂NCH₂)-1-imidazolyl-   347. piperidinyl 2-((CH₃)NHCH₂)-1-imidazolyl-   348. piperidinyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl-   349. piperidinyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl-   350. piperidinyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl-   351. piperidinyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl-   352. piperidinyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl-   353. piperidinyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl-   354. piperidinyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl-   355. piperidinyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl-   356. piperidinyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl-   357. piperidinyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl-   358. piperidinyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl-   359. piperidinyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl-   360. piperidinyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl-   361. piperidinyl isopropyl

Examples 362-6498 use the corresponding A and B groups from Examples1-361 and the recited G group.

Examples 362-722, G is 3-aminoindazol-6-yl;

Examples 723-1083, G is 3-amidophenyl;

Examples 1084-1444, G is 2-(aminomethyl)phenyl;

Examples 1445-1805, G is 3-(aminomethyl)phenyl;

Examples 1806-2166, G is 2-(aminomethyl)-3-fluorophenyl;

Examples 2167-2527, G is 2-(aminomethyl)-4-fluorophenyl;

Examples 2528-2888, G is 4-Cl-2-pyridyl;

Examples 2889-3249, G is 4-chlorophenyl;

Examples 3250-3610, G is 3-amino-4-chloro-phenyl;

Examples 3611-3971, G is 3-amidino-phenyl;

Examples 3972-4332, G is 1-aminoisoquinolin-6-yl;

Examples 4333-4693, G is 1-aminoisoquinolin-7-yl;

Examples 4694-5054, G is 4-aminoquinazol-6-yl;

Examples 5055-5415, G is 4-aminoquinazol-7-yl;

Examples 5416-5776, G is 3-aminobenzisoxazol-5-yl;

Examples 5777-6137, G is 3-aminobenzisoxazol-6-yl; and,

Examples 6138-6498, G is 3-aminoindazol-5-yl.

Table 2

Examples 1-6498 of Table 1, wherein G₁ is NH₂C(O).

Table 3

Examples 1-6498 of Table 1, wherein G₁ is C(O)NH₂.

TABLE 4

-   P₄ is Z-A-B, wherein Z is a bond;-   M₃ is -G₁-G, wherein G₁ is a bond, NH₂C(O), or C(O)NH₂;-   R^(1a) is CH₃;-   G is 4-(methoxy)phenyl;

Ex# A B

-   362. phenyl 2-(NH₂SO₂)phenyl-   363. phenyl 2-(CH₃SO₂)phenyl-   364. phenyl 3-NH₂SO₂₋₄-pyridyl-   365. phenyl 3-CH₃SO₂₋₄-pyridyl-   366. phenyl 2-(CH₃NH)phenyl-   367. phenyl 3-((CH₃)₂NCH₂)-4-pyridyl-   368. phenyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl-   369. phenyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl-   370. phenyl 2-((CH₃)₂NCH₂)phenyl-   371. phenyl 2-((CH₃)NHCH₂)phenyl-   372. phenyl 2-((CH₃CH₂)NHCH₂)phenyl-   373. phenyl 2-((CH₃CH₂)₂NCH₂)phenyl-   374. phenyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl-   375. phenyl 2-(((CH₃)₂CH)NHCH₂)phenyl-   376. phenyl 2-(((CH₃)₂CH)₂NCH₂)phenyl-   377. phenyl 2-((cyclopropyl)NHCH₂)phenyl-   378. phenyl 2-((cyclopropyl)₂NCH₂)phenyl-   379. phenyl 2-((cyclobutyl)NHCH₂)phenyl-   380. phenyl 2-((cyclobutyl)₂NCH₂)phenyl-   381. phenyl 2-((cyclopentyl)NHCH₂)phenyl-   382. phenyl 2-((cyclopentyl)₂NCH₂)phenyl-   383. phenyl 2-((cyclohexyl)NHCH₂)phenyl-   384. phenyl 2-((cyclohexyl)₂NCH₂)phenyl-   385. phenyl 1-CH₃₋₂-imidazolyl-   386. phenyl 2-CH₃₋₁-imidazolyl-   387. phenyl 2-((CH₃)₂NCH₂)-1-imidazolyl-   388. phenyl 2-((CH₃)NHCH₂)-1-imidazolyl-   389. phenyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl-   390. phenyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl-   391. phenyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl-   392. phenyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl-   393. phenyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl-   394. phenyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl-   395. phenyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl-   396. phenyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl-   397. phenyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl-   398. phenyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl-   399. phenyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl-   400. phenyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl-   401. phenyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl-   402. 2-pyridyl 2-(NH₂SO₂)phenyl-   403. 2-pyridyl 2-(CH₃SO₂)phenyl-   404. 2-pyridyl 3-NH₂SO₂₋₄-pyridyl-   405. 2-pyridyl 3-CH₃SO₂₋₄-pyridyl-   406. 2-pyridyl 2-(CH₃NH)phenyl-   407. 2-pyridyl 3-((CH₃)₂NCH₂)-4-pyridyl-   408. 2-pyridyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl-   409. 2-pyridyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl-   410. 2-pyridyl 2-((CH₃)₂NCH₂)phenyl-   411. 2-pyridyl 2-((CH₃)NHCH₂)phenyl-   412. 2-pyridyl 2-((CH₃CH₂)NHCH₂)phenyl-   413. 2-pyridyl 2-((CH₃CH₂)₂NCH₂)phenyl-   414. 2-pyridyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl-   415. 2-pyridyl 2-(((CH₃)₂CH)NHCH₂)phenyl-   416. 2-pyridyl 2-(((CH₃)₂CH)₂NCH₂)phenyl-   417. 2-pyridyl 2-((cyclopropyl)NHCH₂)phenyl-   418. 2-pyridyl 2-((cyclopropyl)₂NCH₂)phenyl-   419. 2-pyridyl 2-((cyclobutyl)NHCH₂)phenyl-   420. 2-pyridyl 2-((cyclobutyl)₂NCH₂)phenyl-   421. 2-pyridyl 2-((cyclopentyl)NHCH₂)phenyl-   422. 2-pyridyl 2-((cyclopentyl)₂NCH₂)phenyl-   423. 2-pyridyl 2-((cyclohexyl)NHCH₂)phenyl-   424. 2-pyridyl 2-((cyclohexyl)₂NCH₂)phenyl-   425. 2-pyridyl 1-CH₃₋₂-imidazolyl-   426. 2-pyridyl 2-CH₃₋₁-imidazolyl-   427. 2-pyridyl 2-((CH₃)₂NCH₂)-1-imidazolyl-   428. 2-pyridyl 2-((CH₃)NHCH₂)-1-imidazolyl-   429. 2-pyridyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl-   430. 2-pyridyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl-   431. 2-pyridyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl-   432. 2-pyridyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl-   433. 2-pyridyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl-   434. 2-pyridyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl-   435. 2-pyridyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl-   436. 2-pyridyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl-   437. 2-pyridyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl-   438. 2-pyridyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl-   439. 2-pyridyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl-   440. 2-pyridyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl-   441. 2-pyridyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl-   442. 3-pyridyl 2-(NH₂SO₂)phenyl-   443. 3-pyridyl 2-(CH₃SO₂)phenyl-   444. 3-pyridyl 3-NH₂SO₂₋₄-pyridyl-   445. 3-pyridyl 3-CH₃SO₂₋₄-pyridyl-   446. 3-pyridyl 2-(CH₃NH)phenyl-   447. 3-pyridyl 3-((CH₃)₂NCH₂)-4-pyridyl-   448. 3-pyridyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl-   449. 3-pyridyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl-   450. 3-pyridyl 2-((CH₃)₂NCH₂)phenyl-   451. 3-pyridyl 2-((CH₃)NHCH₂)phenyl-   452. 3-pyridyl 2-((CH₃CH₂)NHCH₂)phenyl-   453. 3-pyridyl 2-((CH₃CH₂)₂NCH₂)phenyl-   454. 3-pyridyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl-   455. 3-pyridyl 2-(((CH₃)₂CH)NHCH₂)phenyl-   456. 3-pyridyl 2-(((CH₃)₂CH)₂NCH₂)phenyl-   457. 3-pyridyl 2-((cyclopropyl)NHCH₂)phenyl-   458. 3-pyridyl 2-((cyclopropyl)₂NCH₂)phenyl-   459. 3-pyridyl 2-((cyclobutyl)NHCH₂)phenyl-   460. 3-pyridyl 2-((cyclobutyl)₂NCH₂)phenyl-   461. 3-pyridyl 2-((cyclopentyl)NHCH₂)phenyl-   462. 3-pyridyl 2-((cyclopentyl)₂NCH₂)phenyl-   463. 3-pyridyl 2-((cyclohexyl)NHCH₂)phenyl-   464. 3-pyridyl 2-((cyclohexyl)₂NCH₂)phenyl-   465. 3-pyridyl 1-CH₃₋₂-imidazolyl-   466. 3-pyridyl 2-CH₃₋₁-imidazolyl-   467. 3-pyridyl 2-((CH₃)₂NCH₂)-1-imidazolyl-   468. 3-pyridyl 2-((CH₃)NHCH₂)-1-imidazolyl-   469. 3-pyridyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl-   470. 3-pyridyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl-   471. 3-pyridyl 2-((CH₃CH₂) N(H₃)CH₂)-1-imidazolyl-   472. 3-pyridyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl-   473. 3-pyridyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl-   474. 3-pyridyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl-   475. 3-pyridyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl-   476. 3-pyridyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl-   477. 3-pyridyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl-   478. 3-pyridyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl-   479. 3-pyridyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl-   480. 3-pyridyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl-   481. 3-pyridyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl-   482. 2-pyrimidyl 2-(NH₂SO₂)phenyl-   483. 2-pyrimidyl 2-(CH₃SO₂)phenyl-   484. 2-pyrimidyl 3-NH₂SO₂₋₄-pyridyl-   485. 2-pyrimidyl 3-CH₃SO₂₋₄-pyridyl-   486. 2-pyrimidyl 2-(CH₃NH)phenyl-   487. 2-pyrimidyl 3-((CH₃)₂NCH₂)-4-pyridyl-   488. 2-pyrimidyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl-   489. 2-pyrimidyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl-   490. 2-pyrimidyl 2-((CH₃)₂NCH₂)phenyl-   491. 2-pyrimidyl 2-((CH₃)NHCH₂)phenyl-   492. 2-pyrimidyl 2-((CH₃CH₂)NHCH₂)phenyl-   493. 2-pyrimidyl 2-((CH₃CH₂)₂NCH₂)phenyl-   494. 2-pyrimidyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl-   495. 2-pyrimidyl 2-(((CH₃)₂CH)NHCH₂)phenyl-   496. 2-pyrimidyl 2-(((CH₃)₂CH)₂NCH₂)phenyl-   497. 2-pyrimidyl 2-((cyclopropyl)NHCH₂)phenyl-   498. 2-pyrimidyl 2-((cyclopropyl)₂NCH₂)phenyl-   499. 2-pyrimidyl 2-((cyclobutyl)NHCH₂)phenyl-   500. 2-pyrimidyl 2-((cyclobutyl)₂NCH₂)phenyl-   501. 2-pyrimidyl 2-((cyclopentyl)NHCH₂)phenyl-   502. 2-pyrimidyl 2-((cyclopentyl)₂NCH₂)phenyl-   503. 2-pyrimidyl 2-((cyclohexyl)NHCH₂)phenyl-   504. 2-pyrimidyl 2-((cyclohexyl)₂NCH₂)phenyl-   505. 2-pyrimidyl 1-CH₃₋₂-imidazolyl-   506. 2-pyrimidyl 2-CH₃₋₁-imidazolyl-   507. 2-pyrimidyl 2-((CH₃)₂NCH₂)-1-imidazolyl-   508. 2-pyrimidyl 2-((CH₃)NHCH₂)-1-imidazolyl-   509. 2-pyrimidyl 2-((CH₃CH₂)NHCH₂)-1-i-midazolyl-   510. 2-pyrimidyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl-   511. 2-pyrimidyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl-   512. 2-pyrimidyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl-   513. 2-pyrimidyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl-   514. 2-pyrimidyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl-   515. 2-pyrimidyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl-   516. 2-pyrimidyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl-   517. 2-pyrimidyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl-   518. 2-pyrimidyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl-   519. 2-pyrimidyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl-   520. 2-pyrimidyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl-   521. 2-pyrimidyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl-   522. 5-pyrimidyl 2-(NH₂SO₂)phenyl-   523. 5-pyrimidyl 2-(CH₃SO₂)phenyl-   524. 5-pyrimidyl 3-NH₂SO₂₋₄-pyridyl-   525. 5-pyrimidyl 3-CH₃SO₂₋₄-pyridyl-   526. 5-pyrimidyl 2-(CH₃NH)phenyl-   527. 5-pyrimidyl 3-((CH₃)₂NCH₂)-4-pyridyl-   528. 5-pyrimidyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl-   529. 5-pyrimidyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl-   530. 5-pyrimidyl 2-((CH₃)₂NCH₂)phenyl-   531. 5-pyrimidyl 2-((CH₃)NHCH₂)phenyl-   532. 5-pyrimidyl 2-((CH₃CH₂)NHCH₂)phenyl-   533. 5-pyrimidyl 2-((CH₃CH₂)₂NCH₂)phenyl-   534. 5-pyrimidyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl-   535. 5-pyrimidyl 2-(((CH₃)₂CH)NHCH₂)phenyl-   536. 5-pyrimidyl 2-(((CH₃)₂CH)₂NCH₂)phenyl-   537. 5-pyrimidyl 2-((cyclopropyl)NHCH₂)phenyl-   538. 5-pyrimidyl 2-((cyclopropyl)₂NCH₂)phenyl-   539. 5-pyrimidyl 2-((cyclobutyl)NHCH₂)phenyl-   540. 5-pyrimidyl 2-((cyclobutyl)₂NCH₂)phenyl-   541. 5-pyrimidyl 2-((cyclopentyl)NHCH₂)phenyl-   542. 5-pyrimidyl 2-((cyclopentyl)₂NCH₂)phenyl-   543. 5-pyrimidyl 2-((cyclohexyl)NHCH₂)phenyl-   544. 5-pyrimidyl 2-((cyclohexyl)₂NCH₂)phenyl-   545. 5-pyrimidyl 1-CH₃₋₂-imidazolyl-   546. 5-pyrimidyl 2-CH₃₋₁-imidazolyl-   547. 5-pyrimidyl 2-((CH₃)₂NCH₂)-1-imidazolyl-   548. 5-pyrimidyl 2-((CH₃)NHCH₂)-1-imidazolyl-   549. 5-pyrimidyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl-   550. 5-pyrimidyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl-   551. 5-pyrimidyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl-   552. 5-pyrimidyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl-   553. 5-pyrimidyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl-   554. 5-pyrimidyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl-   555. 5-pyrimidyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl-   556. 5-pyrimidyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl-   557. 5-pyrimidyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl-   558. 5-pyrimidyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl-   559. 5-pyrimidyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl-   560. 5-pyrimidyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl-   561. 5-pyrimidyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl-   562. 2-C1-phenyl 2-(NH₂So₂)phenyl-   563. 2-C1-phenyl 2-(CH₃SO₂)phenyl-   564. 2-C1-phenyl 3-NH₂SO₂₋₄-pyridyl-   565. 2-C1-phenyl 3-CH₃SO₂₋₄-pyridyl-   566. 2-C1-phenyl 2-(CH₃NH)phenyl-   567. 2-C1-phenyl 3-((CH₃)₂NCH₂)-4-pyridyl-   568. 2-C1-phenyl 2-(N-(3-R-HO-pyrrolidinyl)CH₂)phenyl-   569. 2-C1-phenyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl-   570. 2-C1-phenyl 2-((CH₃)₂NCH₂)phenyl-   571. 2-C1-phenyl 2-((CH₃)NHCH₂)phenyl-   572. 2-C1-phenyl 2-((CH₃CH₂)NHCH₂)phenyl-   573. 2-C1-phenyl 2-((CH₃CH₂)₂NCH₂)phenyl-   574. 2-C1-phenyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl-   575. 2-C1-phenyl 2-(((CH₃)₂CH)NHCH₂)phenyl-   576. 2-C1-phenyl 2-(((CH₃)₂CH)₂NCH₂)phenyl-   577. 2-C1-phenyl 2-((cyclopropyl)NHCH₂)phenyl-   578. 2-C1-phenyl 2-((cyclopropyl)₂NCH₂)phenyl-   579. 2-C1-phenyl 2-((cyclobutyl)NHCH₂)phenyl-   580. 2-C1-phenyl 2-((cyclobutyl)₂NCH₂)phenyl-   581. 2-C1-phenyl 2-((cyclopentyl)NHCH₂)phenyl-   582. 2-C1-phenyl 2-((cyclopentyl)₂NCH₂)phenyl-   583. 2-C1-phenyl 2-((cyclohexyl)NHCH₂)phenyl-   584. 2-C1-phenyl 2-((cyclohexyl)₂NCH₂)phenyl-   585. 2-C1-phenyl 1-CH₃₋₂-imidazolyl-   586. 2-C1-phenyl 2-CH₃₋₁-imidazolyl-   587. 2-C1-phenyl 2-((CH₃)₂NCH₂)-1-imidazolyl-   588. 2-C1-phenyl 2-((CH₃)NHCH₂)-1-imidazolyl-   589. 2-C1-phenyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl-   590. 2-C1-phenyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl-   591. 2-C1-phenyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl-   592. 2-C1-phenyl 2-((CH₃)₂C)NH)CH₂)-1-imidazolyl-   593. 2-C1-phenyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl-   594. 2-C1-phenyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl-   595. 2-C1-phenyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl-   596. 2-C1-phenyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl-   597. 2-C1-phenyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl-   598. 2-C1-phenyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl-   599. 2-C1-phenyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl-   600. 2-C1-phenyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl-   601. 2-C1-phenyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl-   602. 2-F-phenyl 2-(NH₂SO₂)phenyl-   603. 2-F-phenyl 2-(CH₃SO₂)phenyl-   604. 2-F-phenyl 3-NH₂SO₂₋₄-pyridyl-   605. 2-F-phenyl 3-CH₃SO₂₋₄-pyridyl-   606. 2-F-phenyl 2-(CH₃NH)phenyl-   607. 2-F-phenyl 3-((CH₃)₂NCH₂)-4-pyridyl-   608. 2-F-phenyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl-   609. 2-F-phenyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl-   610. 2-F-phenyl 2-((CH₃)₂NCH₂)phenyl-   611. 2-F-phenyl 2-((CH₃)NHCH₂)phenyl-   612. 2-F-phenyl 2-((CH₃CH₂)NHCH₂)phenyl-   613. 2-F-phenyl 2-((CH₃CH₂)₂NCH₂)phenyl-   614. 2-F-phenyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl-   615. 2-F-phenyl 2-(((CH₃)₂CH)NHCH₂)phenyl-   616. 2-F-phenyl 2-(((CH₃)₂CH)₂NCH₂)phenyl-   617. 2-F-phenyl 2-((cyclopropyl)NHCH₂)phenyl-   618. 2-F-phenyl 2-((cyclopropyl)₂NCH₂)phenyl-   619. 2-F-phenyl 2-((cyclobutyl)NHCH₂)phenyl-   620. 2-F-phenyl 2-((cyclobutyl)₂NCH₂)phenyl-   621. 2-F-phenyl 2-((cyclopentyl)NHCH₂)phenyl-   622. 2-F-phenyl 2-((cyclopentyl)₂NCH₂)phenyl-   623. 2-F-phenyl 2-((cyclohexyl)NHCH₂)phenyl-   624. 2-F-phenyl 2-((cyclohexyl)₂NCH₂)phenyl-   625. 2-F-phenyl 1-CH₃₋₂-imidazolyl-   626. 2-F-phenyl 2-CH₃₋₁-imidazolyl-   627. 2-F-phenyl 2-((CH₃)₂NCH₂)-1-imidazolyl-   628. 2-F-phenyl 2-((CH₃)NHCH₂)-1-imidazolyl-   629. 2-F-phenyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl-   630. 2-F-phenyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl-   631. 2-F-phenyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl-   632. 2-F-phenyl 2-((((CH₃)₂CH)NHCH₂)-1-imidazolyl-   633. 2-F-phenyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl-   634. 2-F-phenyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl-   635. 2-F-phenyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl-   636. 2-F-phenyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl-   637. 2-F-phenyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl-   638. 2-F-phenyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl-   639. 2-F-phenyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl-   640. 2-F-phenyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl-   641. 2-F-phenyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl-   642. 2,6-diF-phenyl 2-(NH₂SO₂)phenyl-   643. 2,6-diF-phenyl 2-(CH₃SO₂)phenyl-   644. 2,6-diF-phenyl 3-NH₂SO₂₋₄-pyridyl-   645. 2,6-diF-phenyl 3-CH₃SO₂₋₄-pyridyl-   646. 2,6-diF-phenyl 2-(CH₃NH)phenyl-   647. 2,6-diF-phenyl 3-((CH₃)₂NCH₂)-4-pyridyl-   648. 2,6-diF-phenyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl-   649. 2,6-diF-phenyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl-   650. 2,6-diF-phenyl 2-((CH₃)₂NCH₂)phenyl-   651. 2,6-diF-phenyl 2-((CH₃)NHCH₂)phenyl-   652. 2,6-diF-phenyl 2-((CH₃CH₂)NHCH₂)phenyl-   653. 2,6-diF-phenyl 2-((CH₃CH₂)₂NCH₂)phenyl-   654. 2,6-diF-phenyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl-   655 .2,6-diF-phenyl 2-(((CH₃)₂CH) NHCH₂)phenyl-   656. 2,6-diF-phenyl 2-(((CH₃)₂CH)₂NCH₂)phenyl-   657. 2,6-diF-phenyl 2-((cyclopropyl)NHCH₂)phenyl-   658. 2,6-diF-phenyl 2-((cyclopropyl)₂NCH₂)phenyl-   659. 2,6-diF-phenyl 2-((cyclobutyl)NHCH₂)phenyl-   660. 2,6-diF-phenyl 2-((cyclobutyl)₂NCH₂)phenyl-   661. 2,6-diF-phenyl 2-((cyclopentyl)NHCH₂)phenyl-   662. 2,6-diF-phenyl 2-((cyclopentyl)₂NCH₂)phenyl-   663. 2,6-diF-phenyl 2-((cyclohexyl)NHCH₂)phenyl-   664. 2,6-diF-phenyl 2-((cyclohexyl)₂NCH₂)phenyl-   665. 2,6-diF-phenyl 1-CH₃₋₂-imidazolyl-   666. 2,6-diF-phenyl 2-CH₃₋₁-imidazolyl-   667. 2,6-diF-phenyl 2-((CH₃)₂NCH₂)-1-imidazolyl-   668. 2,6-diF-phenyl 2-((CH₃)NHCH₂)-1-imidazolyl-   669. 2,6-diF-phenyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl-   670. 2,6-diF-phenyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl-   671. 2,6-diF-phenyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl-   672. 2,6-diF-phenyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl-   673. 2,6-diF-phenyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl-   674. 2,6-diF-phenyl 2-((cyclopropyl)NHCH₂)-1-imidazolyl-   675. 2,6-diF-phenyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl-   676. 2,6-diF-phenyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl-   677. 2,6-diF-phenyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl-   678. 2,6-diF-phenyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl-   679. 2,6-diF-phenyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl-   680. 2,6-diF-phenyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl-   681. 2,6-diF-phenyl 2-((cyclohexyl)₂NCH₂)-1-imidazolyl-   682. piperidinyl 2-(NH₂SO₂)phenyl-   683. piperidinyl 2-(CH₃SO₂)phenyl-   684. piperidinyl 3-NH₂SO₂₋₄-pyridyl-   685. piperidinyl 3-CH₃SO₂₋₄-pyridyl-   686. piperidinyl 2-(CH₃NH)phenyl-   687. piperidinyl 3-((CH₃)₂NCH₂)-4-pyridyl-   688. piperidinyl 2-(N-(3-R—HO-pyrrolidinyl)CH₂)phenyl-   689. piperidinyl 2-(N-(4-HO-piperidinyl)CH₂)phenyl-   690. piperidinyl 2-((CH₃)₂NCH₂)phenyl-   691. piperidinyl 2-((CH₃)NHCH₂)phenyl-   692. piperidinyl 2-((CH₃CH₂)NHCH₂)phenyl-   693. piperidinyl 2-((CH₃CH₂)₂NCH₂)phenyl-   694. piperidinyl 2-((CH₃CH₂)N(CH₃)CH₂)phenyl-   695. piperidinyl 2-(((CH₃)₂CH)NHCH₂)phenyl-   696. piperidinyl 2-(((CH₃)₂CH)₂NCH₂)phenyl-   697. piperidinyl 2-((cyclopropyl)NHCH₂)phenyl-   698. piperidinyl 2-((cyclopropyl)₂NCH₂)phenyl-   699. piperidinyl 2-((cyclobutyl)NHCH₂)phenyl-   700. piperidinyl 2-((cyclobutyl)₂NCH₂)phenyl-   701. piperidinyl 2-((cyclopentyl)NHCH₂)phenyl-   702. piperidinyl 2-((cyclopentyl)₂NCH₂)phenyl-   703. piperidinyl 2-((cyclohexyl)NHCH₂)phenyl-   704. piperidinyl 2-((cyclohexyl)₂NCH₂)phenyl-   705. piperidinyl 1-CH₃₋₂-imidazolyl-   706. piperidinyl 2-CH₃₋₁-imidazolyl-   707. piperidinyl 2-((CH₃)₂NCH₂)-1-imidazolyl-   708. piperidinyl 2-((CH₃)NHCH₂)-1-imidazolyl-   709. piperidinyl 2-((CH₃CH₂)NHCH₂)-1-imidazolyl-   710. piperidinyl 2-((CH₃CH₂)₂NCH₂)-1-imidazolyl-   711. piperidinyl 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl-   712. piperidinyl 2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl-   713. piperidinyl 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl-   714. piperidinyl 2-((cyclopropyl)NHCH₂) -1-imidazolyl-   715. piperidinyl 2-((cyclopropyl)₂NCH₂)-1-imidazolyl-   716. piperidinyl 2-((cyclobutyl)NHCH₂)-1-imidazolyl-   717. piperidinyl 2-((cyclobutyl)₂NCH₂)-1-imidazolyl-   718. piperidinyl 2-((cyclopentyl)NHCH₂)-1-imidazolyl-   719. piperidinyl 2-((cyclopentyl)₂NCH₂)-1-imidazolyl-   720. piperidinyl 2-((cyclohexyl)NHCH₂)-1-imidazolyl-   721. piperidinyl 2-((cyclohexyl)₂NCH2)-1-imidazolyl-   722. piperidinyl isopropyl

Examples 362-6498 use the corresponding A and B groups from Examples1-361 and the recited G group.

Examples 362-722, G is 3-aminoindazol-6-yl;

Examples 723-1083, G is 3-amidophenyl;

Examples 1084-1444, G is 2-(aminomethyl)phenyl;

Examples 1445-1805, G is 3-(aminomethyl)phenyl;

Examples 1806-2166, G is 2-(aminomethyl)-3-fluorophenyl;

Examples 2167-2527, G is 2-(aminomethyl)-4-fluorophenyl;

Examples 2528-2888, G is 4-Cl-2-pyridyl;

Examples 2889-3249, G is 4-chlorophenyl;

Examples 3250-3610, G is 3-amino-4-chloro-phenyl;

Examples 3611-3971, G is 3-amidino-phenyl;

Examples 3972-4332, G is 1-aminoisoquinolin-6-yl;

Examples 4333-4693, G is 1-aminoisoquinolin-7-yl;

Examples 4694-5054, G is 4-aminoquinazol-6-yl;

Examples 5055-5415, G is 4-aminoquinazol-7-yl;

Examples 5416-5776, G is 3-aminobenzisoxazol-5-yl;

Examples 5777-6137, G is 3-aminobenzisoxazol-6-yl; and,

Examples 6138-6498, G is 3-aminoindazol-5-yl.

Table 5

Examples 1-6498 are the same as in Table 4, except that R^(1a) isCH₂CH₃.

Table 6

Examples 1-6498 are the same as in Table 4, except that R^(1a) is CF₃.

Table 7

Examples 1-6498 are the same as in Table 4, except that R^(1a) is SCH₃.

Table 8

Examples 1-6498 are the same as in Table 4, except that R^(1a) is SOCH₃.

Table 9

Examples 1-6498 are the same as in Table 4, except that R^(1a) isSO₂CH₃.

Table 10

Examples 1-6498 are the same as in Table 4, except that R^(1a) is Cl.

Table 11

Examples 1-6498 are the same as in Table 4, except that R^(1a) is F.

Table 12

Examples 1-6498 are the same as in Table 4, except that R^(1a) isCO₂CH₃.

Table 13

Examples 1-6498 are the same as in Table 4, except that R^(1a) CH₂OCH₃.

Table 14

Examples 1-6498 are the same as in Table 4, except that R^(1a) is CONH₂.

Table 15

Examples 1-6498 are the same as in Table 4, except that R^(1a) is CN.

Table 16

Examples 1-6498 are the same as in Table 4, except that R^(1a) isCH₂NH₂.

Table 17

Examples 1-6498 are the same as in Table 4, except that R^(1a) isCH₂NHSO₂CH₃.

Utility

The compounds of this invention are useful as anticoagulants for thetreatment or prevention of thromboembolic disorders in mammals. Ingeneral, a thromboembolic disorder is a circulatory disease caused byblood clots (i.e., diseases involving platelet activation and/orplatelet aggregation). The term “thromboembolic disorders” as usedherein includes arterial cardiovascular thromboembolic disorders, venouscardiovascular thromboembolic disorders, arterial cerebrovascularthromboembolic disorders, and venous cerebrovascular thromboembolicdisorders. The term “thromboembolic disorders” as used herein includesspecific disorders selected from, but not limited to, unstable angina,first myocardial infarction, recurrent myocardial infarction, ischemicsudden death, transient ischemic attack, stroke, atherosclerosis, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom (a) prosthetic valves or other implants, (b) indwelling catheters,(c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) otherprocedures in which blood is exposed to an artificial surface thatpromotes thrombosis. It is noted that thrombosis includes occlusion(e.g. after a bypass) and reocclusion (e.g., during or afterpercutaneous translumianl coronary angioplasty). The anticoagulanteffect of compounds of the present invention is believed to be due toinhibition of factor Xa or thrombin.

The effectiveness of compounds of the present invention as inhibitors offactor Xa was determined using purified human factor Xa and syntheticsubstrate. The rate of factor Xa hydrolysis of chromogenic substrateS2222 (Diapharma/Chromogenix, West Chester, Ohio) was measured both inthe absence and presence of compounds of the present invention.Hydrolysis of the substrate resulted in the release of pNA, which wasmonitored spectrophotometrically by measuring the increase in absorbanceat 405 nM. A decrease in the rate of absorbance change at 405 nm in thepresence of inhibitor is indicative of enzyme inhibition. The results ofthis assay are expressed as inhibitory constant, K_(i).

Factor Xa determinations were made in 0.10 M sodium phosphate buffer, pH7.5, containing 0.20 M NaCl, and 0.5% PEG 8000. The Michaelis constant,K_(m), for substrate hydrolysis was determined at 25° C. using themethod of Lineweaver and Burk. Values of K_(i) were determined byallowing 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, SouthBend, Ind.) to react with the substrate (0.20 mM-1 mM) in the presenceof inhibitor. Reactions were allowed to go for 30 minutes and thevelocities (rate of absorbance change vs time) were measured in the timeframe of 25-30 minutes. The following relationship was used to calculateK_(i) values:(v _(o) −v _(s))/v _(s) =I/(K _(i)(1+S/K _(m)))where:

-   -   v_(o) is the velocity of the control in the absence of        inhibitor;    -   v_(s) is the velocity in the presence of inhibitor;    -   I is the concentration of inhibitor;    -   K_(i i)s the dissociation constant of the enzyme:inhibitor        complex;    -   S is the concentration of substrate;    -   K_(m) is the Michaelis constant.

Compounds tested in the above assay are considered to be active if theyexhibit a K_(i) of ≦10 μM. Preferred compounds of the present inventionhave K_(i)'s of ≦1 μM. More preferred compounds of the present inventionhave K₁'s of ≦0.1 μM. Even more preferred compounds of the presentinvention have K_(i)'s of ≦0.01 μM. Still more preferred compounds ofthe present invention have K_(i)'s of ≦0.001 μM. Using the methodologydescribed above, a number of compounds of the present invention werefound to exhibit K_(i)'s of ≦10 μM, thereby confirming the utility ofthe compounds of the present invention as effective Xa inhibitors.

The antithrombotic effect of compounds of the present invention can bedemonstrated in a rabbit arterio-venous (AV) shunt thrombosis model. Inthis model, rabbits weighing 2-3 kg anesthetized with a mixture ofxylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used. Asaline-filled AV shunt device is connected between the femoral arterialand the femoral venous cannulae. The AV shunt device consists of a pieceof 6-cm tygon tubing that contains a piece of silk thread. Blood willflow from the femoral artery via the AV-shunt into the femoral vein. Theexposure of flowing blood to a silk thread will induce the formation ofa significant thrombus. After forty minutes, the shunt is disconnectedand the silk thread covered with thrombus is weighed. Test agents orvehicle will be given (i.v., i.p., s.c., or orally) prior to the openingof the AV shunt. The percentage inhibition of thrombus formation isdetermined for each treatment group. The ID₅₀ values (dose whichproduces 50% inhibition of thrombus formation) are estimated by linearregression.

The compounds of the present invention may also be useful as inhibitorsof serine proteases, notably human thrombin, Factor VIIa, Factor IXa,plasma kallikrein and plasmin. Because of their inhibitory action, thesecompounds are indicated for use in the prevention or treatment ofphysiological reactions, blood coagulation and inflammation, catalyzedby the aforesaid class of enzymes. Specifically, the compounds haveutility as drugs for the treatment of diseases arising from elevatedthrombin activity such as myocardial infarction, and as reagents used asanticoagulants in the processing of blood to plasma for diagnostic andother commercial purposes.

Some compounds of the present invention were shown to be direct actinginhibitors of the serine protease thrombin by their ability to inhibitthe cleavage of small molecule substrates by thrombin in a purifiedsystem. In vitro inhibition constants were determined by the methoddescribed by Kettner et al. in J. Biol. Chem. 265, 18289-18297 (1990),herein incorporated by reference. In these assays, thrombin-mediatedhydrolysis of the chromogenic substrate S2238 (Helena Laboratories,Beaumont, Tex.) was monitored spectrophotometrically. Addition of aninhibitor to the assay mixture results in decreased absorbance and isindicative of thrombin inhibition. Human thrombin (Enzyme ResearchLaboratories, Inc., South Bend, Ind.) at a concentration of 0.2 nM in0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% PEG 6000,was incubated with various substrate concentrations ranging from 0.20 to0.02 mM. After 25 to 30 minutes of incubation, thrombin activity wasassayed by monitoring the rate of increase in absorbance at 405 nm thatarises owing to substrate hydrolysis. Inhibition constants were derivedfrom reciprocal plots of the reaction velocity as a function ofsubstrate concentration using the standard method of Lineweaver andBurk. Using the methodology described above, some compounds of thisinvention were evaluated and found to exhibit a K_(i) of less than 10μm, thereby confirming the utility of the compounds of the presentinvention as effective thrombin inhibitors.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. Theseinclude other anti-coagulant or coagulation inhibitory agents,anti-platelet or platelet inhibitory agents, thrombin inhibitors, orthrombolytic or fibrinolytic agents.

The compounds are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is meant anamount of a compound of the present invention that, when administeredalone or in combination with an additional therapeutic agent to amammal, is effective to prevent or ameliorate the thromboembolic diseasecondition or the progression of the disease.

By “administered in combination” or “combination therapy” it is meantthat a compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect. Other anticoagulant agents (or coagulation inhibitory agents)that may be used in combination with the compounds of this inventioninclude warfarin and heparin (either unfractionated heparin or anycommercially available low molecular weight heparin), syntheticpentasaccharide, direct acting thrombin inhibitors including hirudin andargatrobanas well as other factor Xa inhibitors such as those describedin the publications identified above under Background of the Invention.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, denotes agents that inhibit platelet function such as byinhibiting the aggregation, adhesion or granular secretion of platelets.Such agents include, but are not limited to, the various knownnon-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin,ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam,diclofenac, sulfinpyrazone, and piroxicam, including pharmaceuticallyacceptable salts or prodrugs thereof. Of the NSAIDS, aspirin(acetylsalicyclic acid or ASA), and piroxicam are preferred. Othersuitable anti-platelet agents include ticlopidine and clopidogrel,including pharmaceutically acceptable salts or prodrugs thereof.Ticlopidine and clopidogrel are also preferred compounds since they areknown to be gentle on the gastro-intestinal tract in use. Still othersuitable platelet inhibitory agents include IIb/IIIa antagonists,including tirofiban, eptifibatide, and abciximab,thromboxane-A2-receptor antagonists and thromboxane-A2-synthetaseinhibitors, as well as pharmaceutically acceptable salts or prodrugsthereof.

The term thrombin inhibitors (or anti-thrombin agents), as used herein,denotes inhibitors of the serine protease thrombin. By inhibitingthrombin, various thrombin-mediated processes, such as thrombin-mediatedplatelet activation (that is, for example, the aggregation of platelets,and/or the granular secretion of plasminogen activator inhibitor-1and/or serotonin) and/or fibrin formation are disrupted. A number ofthrombin inhibitors are known to one of skill in the art and theseinhibitors are contemplated to be used in combination with the presentcompounds. Such inhibitors include, but are not limited to, boroargininederivatives, boropeptides, heparins, hirudin, argatroban, andmelagatran, including pharmaceutically acceptable salts and prodrugsthereof. Boroarginine derivatives and boropeptides include N-acetyl andpeptide derivatives of boronic acid, such as C-terminal α-aminoboronicacid derivatives of lysine, ornithine, arginine, homoarginine andcorresponding isothiouronium analogs thereof. The term hirudin, as usedherein, includes suitable derivatives or analogs of hirudin, referred toherein as hirulogs, such as disulfatohirudin.

The term thrombolytics (or fibrinolytic) agents (or thrombolytics orfibrinolytics), as used herein, denotes agents that lyse blood clots(thrombi). Such agents include tissue plasminogen activator and modifiedforms thereof, anistreplase, urokinase or streptokinase, includingpharmaceutically acceptable salts or prodrugs thereof. The termanistreplase, as used herein, refers to anisoylated plasminogenstreptokinase activator complex, as described, for example, in EP028,489, the disclosure of which is hereby incorporated herein byreference herein. The term urokinase, as used herein, is intended todenote both dual and single chain urokinase, the latter also beingreferred to herein as prourokinase.

Administration of the compounds of the present invention in combinationwith such additional therapeutic agent, may afford an efficacy advantageover the compounds and agents alone, and may do so while permitting theuse of lower doses of each. A lower dosage minimizes the potential ofside effects, thereby providing an increased margin of safety.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the inhibition of factor Xa. Such compoundsmay be provided in a commercial kit, for example, for use inpharmaceutical research involving factor Xa. For example, a compound ofthe present invention could be used as a reference in an assay tocompare its known activity to a compound with an unknown activity. Thiswould ensure the experimenter that the assay was being performedproperly and provide a basis for comparison, especially if the testcompound was a derivative of the reference compound. When developing newassays or protocols, compounds according to the present invention couldbe used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving factor Xa. For example, the presence of factor Xa in anunknown sample could be determined by addition of chromogenic substrateS2222 to a series of solutions containing test sample and optionally oneof the compounds of the present invention. If production of pNA isobserved in the solutions containing test sample, but not in thepresence of a compound of the present invention, then one would concludefactor Xa was present.

Dosage and Formulation

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will rangefrom about 1 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl-or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Representative useful pharmaceutical dosage-forms for administration ofthe compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 100 milligrams of active ingredient, 0.2 milligrams of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams ofmicrocrystalline cellulose, 11 milligrams of starch and 98.8 milligramsof lactose. Appropriate coatings may be applied to increase palatabilityor delay absorption.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution should be made isotonicwith sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P, and 0.025 mL of vanillin.

Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 to100 milligrams of the compound of Formula I and about 1 to 7.5milligrams of the second anticoagulant, per kilogram of patient bodyweight. For a tablet dosage form, the compounds of this inventiongenerally may be present in an amount of about 5 to 10 milligrams perdosage unit, and the second anti-coagulant in an amount of about 1 to 5milligrams per dosage unit.

Where the compounds of the present invention are administered incombination with an anti-platelet agent, by way of general guidance,typically a daily dosage may be about 0.01 to 25 milligrams of thecompound of Formula I and about 50 to 150 milligrams of theanti-platelet agent, preferably about 0.1 to 1 milligrams of thecompound of Formula I and about 1 to 3 milligrams of antiplateletagents, per kilogram of patient body weight.

Where the compounds of Formula I are administered in combination withthrombolytic agent, typically a daily dosage may be about 0.1 to 1milligrams of the compound of Formula I, per kilogram of patient bodyweight and, in the case of the thrombolytic agents, the usual dosage ofthe thrombolyic agent when administered alone may be reduced by about70-80% when administered with a compound of Formula I.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, generally the amount ofeach component in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of Formula I and a second therapeuticagent are combined in a single dosage unit they are formulated such thatalthough the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized (thatis, reduced). For example, one active ingredient may be enteric coated.By enteric coating one of the active ingredients, it is possible notonly to minimize the contact between the combined active ingredients,but also, it is possible to control the release of one of thesecomponents in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but ratheR is released in theintestines. One of the active ingredients may also be coated with amaterial that affects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low-viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Numerous modifications and variations of the present invention arepossible in light of the above teachings. It is therefore to beunderstood that within the scope of the appended claims, the inventionmay be practiced otherwise that as specifically described herein.

1. A compound of formula I:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;ring M is substituted with 0-1 R^(1a) and is selected from the group:

ring P, including P₁, P₂, P₃, and P₄ is:

one of P₄ and M₃ is -Z-A-B and the other -G₁-G; G is a group of formulaIIa or IIb:

ring D, including the two atoms of Ring E to which it is attached, is a5-6 membered non-aromatic ring consisting of carbon atoms, 0-1 doublebonds, and 0-2 heteroatoms selected from the group consisting of N, O,and S(O)_(p), and D is substituted with 0-2 R; alternatively, ring D,including the two atoms of Ring E to which it is attached, is a 5-6membered aromatic system consisting of carbon atoms and 0-2 heteroatomsselected from the group consisting of N, O, and S(O)_(p), and D issubstituted with 0-2 R; E is selected from phenyl, pyridyl, pyrimidyl,pyrazinyl, and pyridazinyl, and is substituted with 1-2 R;alternatively, the bridging portion of ring D is absent, and ring E isselected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl,thienyl, and thiazolyl, and ring E is substituted with 1-2 R; R isselected from H, C₁₋₄ alkyl, F, Cl, Br, I, OH, OCH₃, OCH₂CH₃, OCH(CH₃)₂,OCH₂CH₂CH₃, CN, C(═NR⁸)NR⁷R⁹, NHC(═NR⁸)NR⁷R⁹, NR⁸CH(═NR⁷), NH₂, NH(C₁₋₃alkyl), N(C₁₋₃ alkyl)₂, C(═NH)NH₂, CH₂NH₂, CH₂NH(C₁₋₃ alkyl), CH₂N(C₁₋₃alkyl)₂, CH₂CH₂NH₂, CH₂CH₂NH(C₁₋₃ alkyl), CH₂CH₂N(C₁₋₃ alkyl)₂,(CR⁸R⁹)_(t)C(O)H, (CR⁸R⁹)_(t)C(O)R^(2c), (CR⁸R⁹)_(t)NR⁷R⁸,(CR⁸R⁹)_(t)C(O)NR⁷R⁸, (CR⁸R⁹)_(t)NR⁷C(O)R⁷, (CR⁸R⁹)_(t)OR³,(CR⁸R⁹)_(t)S(O)_(p)NR⁷R⁸, (CR⁸R⁹)_(t)NR⁷S(O)_(p)R⁷, (CR⁸R⁹)_(t)SR³,(CR⁸R⁹)_(t)S(O)R³, (CR⁸R⁹)_(t)S(O)₂R³, and OCF₃, provided thatS(O)_(p)R⁷ forms other than S(O)₂H or S(O)H; alternatively, when 2 Rgroups are attached to adjacent atoms, they combine to formmethylenedioxy or ethylenedioxy; A is selected from: C₃₋₁₀ carbocyclesubstituted with 0-2 R⁴, and 5-12 membered heterocycle consisting of:carbon atoms and 1-4 heteroatoms selected from the group consisting ofN, O, and S(O)_(p) substituted with 0-2 R⁴; B is selected from phenyl,pyrrolidino, N-pyrrolidino-carbonyl morpholino, N-morpholino-carbonyl,1,2,3-triazolyl, imidazolyl, and benzimidazolyl, and is substituted with0-1 R^(4a); G₁ is absent or is selected from (CR³R^(3a))₁₋₅,(CR³R^(3a))₀₋₂CR³═CR³(CR³R^(3a))₀₋₂, (CR³R^(3a))₀₋₂, C≡C(CR³R^(3a))₀₋₂,(CR³R^(3a))_(u)C(O)(CR³R^(3a))_(w), (CR³R^(3a))_(u)C(O)O(CR³R^(3a))_(w),(CR³R^(3a))_(u)O(CR³R^(3a))_(w), (CR³R^(3a))_(u)NR³(CR³R^(3a))_(w),(CR³R^(3a))_(u)C(O)NR³(CR³R^(3a))_(w), (CR³R^(3a))_(u)NR³C(O)(CR³R^(3a))_(w), (CR³R^(3a))_(u)OC(O)NR³(CR³R^(3a))_(w),(CR³R^(3a))_(u)NR³C(O)O(CR³R^(3a))_(w),(CR³R^(3a))_(u)NR³C(O)NR³(CR³R^(3a))_(w),(CR³R^(3a))_(u)NR³C(S)NR³(CR³R^(3a))_(w),(CR³R^(3a))_(u)S(CR³R^(3a))_(w), (CR³R^(3a))_(u)S(O)(CR³R^(3a))_(w),(CR³R^(3a))_(u)S(O)₂(CR³R^(3a))_(w),(CR³R^(3a))_(u)S(O)NR³(CR³R^(3a))_(w),(CR³R^(3a))_(u)NR³S(O)₂(CR³R^(3a))_(w),(CR³R^(3a))_(u)S(O)₂NR³(CR³R^(3a))_(w), and(CR³R^(3a))_(u)NR³S(O)₂NR³(CR³R^(3a))_(w), wherein u+w total 0, 1, 2, 3,or 4, provided that G₁ does not form a N—N, N—O, N—S, NCH₂N, NCH₂O, orNCH₂S bond with either group to which it is attached; Z is selected froma bond, —(CR²R^(2a))₁₋₄—, (CR²R^(2a))_(q)O(CR²R^(2a))_(q1),(CR²R^(2a))_(q)NR³(CR²R^(2a))_(q1), (CR²R^(2a))_(q)C(O)(CR²R^(2a))_(q1),(CR²R^(2a))_(q)C(O)O(CR²R^(2a))_(q1),(CR²R^(2a))_(q)OC(O)(CR²R^(2a))_(q1),(CR²R^(2a))_(q)C(O)NR³(CR²R^(2a))_(q1),(CH₂)_(q)NR³C(O)(CR²R^(2a))_(q1), (CR²R^(2a))_(q)OC(O)O(CR²R^(2a))_(q1),(CH₂)_(q)OC(O)NR³(CR²R^(2a))_(q1),(CR²R^(2a))_(q)NR³C(O)O(CR²R^(2a))_(q1),(CH₂)_(q)NR³C(O)NR³(CR²R^(2a))_(q1), (CR²R^(2a))_(q)S(CR²R^(2a))_(q1),(CR²R^(2a))_(q)S(O)(CR²R^(2a))_(q1), (CH₂)_(q)S(O)₂(CR²R^(2a))_(q1),(CR²R^(2a))_(q)SO₂NR³(CR²R^(2a))_(q1), (CH₂)_(q)NR³SO₂(CR²R^(2a))_(q1),and (CR²R^(2a))_(q)NR³SO₂NR³(CR²R^(2a))_(q1), wherein q+q1 total 0, 1,or 2, provided that Z does not form a N—N, N—O, N—S, NCH₂N, NCH₂O, orNCH₂S bond with either group to which it is attached; R^(1a) is selectedfrom H, —(CH₂)_(r)—R^(1b), —CH═CH—R^(1b), NCH₂R^(1c), OCH₂R^(1c),SCH₂R^(1c), NH(CH₂)₂(CH₂)_(t)R^(1b), O(CH₂)₂(CH₂)_(t)R^(1b),S(CH₂)₂(CH₂)_(t)R^(1b), S(O)_(p)(CH₂)_(r)R^(1d), O(CH₂)_(r)R^(1d),NR³(CH₂)_(r)R^(1d), OC(O)NR³(CH₂)_(r)R^(1d), NR³C(O)NR³(CH₂)_(r)R^(1d),NR³C(O)O(CH₂)_(r)R^(1d), and NR³C(O)(CH₂)_(r)R^(1d), provided thatR^(1a) forms other than an N-halo, N—N, N—S, N—O, or N—CN bond; R^(1b)is selected from H, C₁₋₃ alkyl, F, Cl, Br, I, —CN, —CHO, (CF₂)_(r)CF₃,(CH₂)_(r)OR², NR²R^(2a), C(O)R^(2c), OC(O)R², (CF₂)_(r)CO₂R^(2a),S(O)_(p)R^(2b), NR²(CH₂)_(r)OR², C(═NR²C)NR²R^(2a), NR²C(O)R^(2b),NR²C(O)NHR^(2b), NR²C(O)₂R^(2a), OC(O)NR^(2a)R^(2b), C(O)NR²R^(2a),C(O)NR²(CH₂)_(r)OR², SO₂NR²R^(2a), NR²SO₂R^(2b), C₃₋₆ carbocyclesubstituted with 0-2 R^(4a), and 5-10 membered heterocycle consisting ofcarbon atoms and from 1-4 heteroatoms selected from the group consistingof N, O, and S(O)_(p) substituted with 0-2 R^(4a), provided that R^(1b)forms other than an N-halo, N—N, N—S, N—O, or N—CN bond; R^(1c) isselected from H, CH(CH₂OR²)₂, C(O)R^(2c), C(O)NR²R^(2a), S(O)R^(2b),S(O)₂R^(2b), and SO₂NR²R^(2a); R^(1d) is selected from C₃₋₆ carbocyclesubstituted with 0-2 R^(4a) and 5-10 membered heterocycle consisting ofcarbon atoms and from 1-4 heteroatoms selected from the group consistingof N, O, and S(O)_(p) substituted with 0-2 R^(4a), provided that R^(id)forms other than an N—N, N—S, or N—O bond; R², at each occurrence, isselected from H, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocycle substitutedwith 0-2 R^(4b), a C₃₋₆ carbocycle-CH₂— substituted with 0-2 R^(4b), and5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatomsselected from the group consisting of N, O, and S(O)_(p) substitutedwith 0-2 R^(4b); R^(2a), at each occurrence, is selected from H, CF₃,C₁₋₆ alkyl, benzyl, C₃₋₆ carbocycle substituted with 0-2 R^(4b), and 5-6membered heterocycle consisting of: carbon atoms and 1-4 heteroatomsselected from the group consisting of N, O, and S(O)_(p) substitutedwith 0-2 R^(4b); R^(2b), at each occurrence, is selected from CF₃, C₁₋₄alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocycle substituted with 0-2 R^(4b),and 5-6 membered heterocycle consisting of: carbon atoms and 1-4heteroatoms selected from the group consisting of N, O, and S(O)_(p)substituted with 0-2 R^(4b); R^(2c), at each occurrence, is selectedfrom CF₃, OH, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclesubstituted with 0-2 R^(4b), and 5-6 membered heterocyclic systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S(O)_(p) substituted with 0-2 R^(4b); alternatively, R² andR^(2a), together with the atom to which they are attached, combine toform a 5 or 6 membered saturated, partially saturated or unsaturatedring substituted with 0-2 R^(4b) and consisting of: 0-1 additionalheteroatoms selected from the group consisting of N, O, and S(O)_(p);R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;R^(3a), at each occurrence, is selected from H, C₁₋₄ alkyl, benzyl, andphenyl; R^(3b), at each occurrence, is selected from H, C₁₋₄ alkyl, andphenyl; R^(3c), at each occurrence, is selected from C₁₋₄ alkyl, benzyl,and phenyl; R^(3d), at each occurrence, is selected from H, C₁₋₄ alkyl,C₁₋₄ alkyl-phenyl, and C(═O)R^(3c); R⁴, at each occurrence, is selectedfrom H, ═O, (CH₂)_(r)OR², F, Cl, Br, I, C₁₋₄ alkyl, —CN, NO₂,(CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b), C(O)NR²R^(2a),NR²C(O)NR²R^(2a), C(═NR²)NR²R^(2a), C(═NS(O)₂R⁵)NR²R^(2a),NHC(═NR²)NR²R^(2a), C(O)NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a),NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, (CF₂)_(r)CF₃,NCH₂R^(1c), OCH₂R^(1c), SCH₂R^(1c), N(CH₂)₂(CH₂)_(t)R^(1b),O(CH₂)₂(CH₂)_(t)R^(1b), and S(CH₂)₂(CH₂)_(t)R^(1b); alternatively, oneR⁴ is a 5-6 membered aromatic heterocycle consisting of: carbon atomsand 1-4 heteroatoms selected from the group consisting of N, O, andS(O)_(p); R^(4a), at each occurrence, is selected from H, ═O,(CH₂)_(r)OR², (CH₂)_(r)—F, (CH₂)_(r)—Br, (CH₂)_(r)—Cl, Cl, Br, F, I,C₁₋₄ alkyl, s-CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c),NR²C(O)R^(2b), C(O)NR²R^(2a), (CH₂)_(r)N═CHOR³, C(O)NH(CH₂)₂NR²R^(2a),NR²C(O)NR²R^(2a), C(═NR²)NR²R^(2a), NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a),NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, C(O)NHSO₂—C₁₋₄ alkyl, NR²SO₂R⁵,S(O)_(p)R⁵, and (CF₂)_(r)CF₃; alternatively, one R^(4a) is phenylsubstituted with 0-1 R⁵ or a 5-6 membered aromatic heterocycleconsisting of: carbon atoms and 1-4 heteroatoms selected from the groupconsisting of N, O, and S(O)_(p) substituted with 0-1 R⁵; R^(4b), ateach occurrence, is selected from H, ═O, (CH₂)_(r)OR³, F, Cl, Br, I,C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³,(CH₂)_(r)C(O)OR^(3c), NR³C(O)R^(3a), C(O)NR³R^(3a), NR³C(O)NR³R^(3a),C(═NR³)NR³R^(3a), NR³C(═NR³)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂NR³R^(3a),NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃, NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄alkyl, S(O)_(p)-phenyl, and (CF₂)_(r)CF₃; R⁵, at each occurrence, isselected from H, C₁₋₆ alkyl, ═O, (CH₂)_(r)OR³, F, Cl, Br, I, C₁₋₄ alkyl,—CN, NO₂, (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³, (CH₂)_(r)C(O)OR^(3c),NR³C(O)R^(3a), C(O)NR³R^(3a), NR³C(O)NR³R^(3a), CH(═NOR^(3d)),C(═NR³)NR³R^(3a), NR³C(═NR³) NR³R^(3a), SO₂NR³R^(3a), NR³SO₂NR³R^(3a),NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃, NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄alkyl, S(O)_(p)-phenyl, (CF₂)_(r)CF₃, phenyl substituted with 0-2 R⁶,naphthyl substituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶;R⁶, at each occurrence, is selected from H, OH, (CH₂)_(r)OR², halo, C₁₋₄alkyl, CN, NO₂, (CH₂)_(r)NR₂R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b),NR²C(O)NR²R^(2a), C(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂NR²R^(2a),and NR²SO₂C₁₋₄ alkyl; R⁷, at each occurrence, is selected from H, OH,C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl,(CH₂)_(n)-phenyl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl,phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl; R⁸, at eachoccurrence, is selected from H, C₁₋₆ alkyl, and (CH₂)_(n)-phenyl;alternatively, R⁷ and R⁸ combine to form a 5 or 6 membered saturated,ring which contains from 0-1 additional heteroatoms selected from thegroup consisting of N, O, and S(O)_(p); R⁹, at each occurrence, isselected from H, C₁₋₆ alkyl, and (CH₂)_(n)-phenyl; n, at eachoccurrence, is selected from 0, 1, 2, and 3; p, at each occurrence, isselected from 0, 1, and 2; r, at each occurrence, is selected from 0, 1,2, 3, 4, 5, and 6; t, at each occurrence, is selected from 0, 1, 2, and3; provided that: (a) when P₄ is -Z-A-B and G is substituted with anamidino, guanidino, amino-ethylene, or amino-propylene group, any ofwhich may be substituted or cyclized, then G₁ is present or Z is otherthan a bond or alkylene; and (b) when P₄ is -G₁-G and G₁ is absent oralkylene, then Z is other than a bond or alkylene.
 2. A compoundaccording to claim 1, wherein: G is selected from the group:

A is selected from one of the following carbocyclic and heterocyclicsystems which are substituted with 0-2 R⁴; phenyl, piperidinyl,piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl,pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl,benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl,indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl; G₁ isabsent or is selected from (CR³R^(3a))₁₋₃,(CR³R^(3a))_(u)C(O)(CR³R^(3a))_(w), (CR³R^(3a))_(u)O(CR³R^(3a))_(w),(CR³R^(3a))_(u)NR³(CR³CR^(3a))_(w),(CR³R^(3a))_(u)C(O)NR³(CR³R^(3a))_(w),(CR³R^(3a))_(u)NR³C(O)(CR³R^(3a))_(w), (CR³R^(3a))_(u)S(CR³R^(3a))_(w),(CR³R^(3a))_(u)S(O)(CR³R^(3a))_(w), (CR³R^(3a))_(u)S(O)₂(CR³R^(3a))_(w),(CR³R^(3a))_(u)S(O)NR³(CR³R^(3a))_(w), and(CR³R^(3a))_(u)S(O)₂NR³(CR³R^(3a))_(w), wherein u+w total 0, 1, or 2,provided that G₁ does not form a N—N, N—O, N—S, NCH₂N, NCH₂O, or NCH₂Sbond with either group to which it is attached; and, Z is selected froma bond, CH₂O, OCH₂, NH, CH₂NH, NHCH₂, CH₂C(O), C(O)CH₂, C(O)NH, NHC(O),CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and NHSO₂, provided that Z does not form aN—N, N—O, N—S, NCH₂N, NCH₂O, or NCH₂S bond with either group to which itis attached.
 3. A compound according to claim 2, wherein: G is selectedfrom the group:

G₁ is absent or is selected from CH₂, CH₂CH₂, CH₂O, OCH₂, NH, CH₂NH,NHCH₂, CH₂C(O), C(O)CH₂, C(O)NH, NHC(O), CH₂S(O)₂, S(O)₂(CH₂), SO₂NH,and NHSO₂, provided that G₁ does not form a N—N, N—O, N—S, NCH₂N, NCH₂O,or NCH₂S bond with either group to which it is attached; and, Z isselected from a bond, CH₂O, OCH₂, NH, CH₂NH, NHCH₂, CH₂C(O), C(O)CH₂,C(O)NH, NHC(O), CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and NHSO₂, provided that Zdoes not form a N—N, N—O, N—S, NCH₂N, NCH₂O, or NCH₂S bond with eithergroup to which it is attached.
 4. A compound according to claim 3,wherein: G is selected from:

G₁ is absent.
 5. A compound according to claim 4, wherein: A is selectedfrom phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R⁴; R²,at each occurrence, is selected from H, CH₃, CH₂CH₃, cyclopropylmethyl,cyclobutyl, and cyclopentyl; R_(2a), at each occurrence, is H or CH₃;alternatively, R² and R^(2a), together with the atom to which they areattached, combine to form pyrrolidine substituted with 0-2 R^(4b) orpiperidine substituted with 0-2 R^(4b); R⁴, at each occurrence, isselected from OH, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a),and (CF₂)_(r)CF₃; R^(4a) is selected from C₁₋₄ alkyl, CF₃, (CH₂)_(r)OR²,(CH₂)_(r)NR²R^(2a), S(O)_(p)R⁵, SO₂NR²R^(2a), and 1-CF₃-tetrazol-2-yl;R^(4b), at each occurrence, is selected from H, CH₃, and OH; R⁵, at eachoccurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, and benzyl; and,r, at each occurrence, is selected from 0, 1, and
 2. 6. A compoundaccording to claim 5, wherein: A is selected from the group: phenyl,2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl,3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and, Bis selected from the group: 2-(aminosulfonyl)phenyl,2-(methylaminosulfonyl)phenyl, 1 -pyrrolidinocarbonyl,2-(methylsulfonyl)phenyl, 2-(N,N-dimethylaminomethyl)phenyl,2-(N-methylaminomethyl)phenyl, 2-(N-ethyl-N-methylaminomethyl)phenyl,2-(N-pyrrolidinylmethyl)phenyl, 1-methyl-2-imidazolyl,2-methyl-1-imidazolyl, 2-(dimethylaminomethyl)-1-imidazolyl,2-(methylaminomethyl)-1-imidazolyl,2-(N-(cyclopropylmethyl)aminomethyl)phenyl,2-(N-(cyclobutyl)aminomethyl)phenyl,2-(N-(cyclopentyl)aminomethyl)phenyl,2-(N-(4-hydroxypiperidinyl)methyl)phenyl, and2-(N-(3-hydroxypyrrolidinyl)methyl)phenyl.
 7. A compound selected fromthe group:

wherein: R^(1a) is selected from CH₃, CH₂CH₃, CF₃, SCH₃, SOCH₃, SO₂CH₃,Cl, F, CO₂CH₃, CH₂OCH₃, CONH₂, CN, CH₂NH₂, and CH₂NHSO₂CH₃; P₄ is Z-A-B;Z is a bond; M₃ is -G₁-G; G₁ is selected from a bond, NHC(O), andC(O)NH; A is selected from phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl,5-pyrimidyl, 2-Cl-phenyl, 2-F-pheny, 2,6-diF-phenyl, and piperidinyl; Bis selected from 2-(NH₂SO₂)phenyl, 2-(CH₃SO₂)phenyl, 3-NH₂SO₂-4-pyridyl,3-CH₃SO₂-4-pyridyl, 2-(CH₃NH)phenyl, 3-((CH₃)₂NCH₂)-4-pyridyl,2-(N-(3-R-HO-pyrrolidinyl)CH₂)phenyl, 2-(N-(4-HO-piperidinyl)CH₂)phenyl,2-((CH₃)₂NCH₂)phenyl, 2-((CH₃)NHCH₂)phenyl, 2-((CH₃CH₂)NHCH₂)phenyl,2-((CH₃CH₂)₂NCH₂)phenyl, 2-((CH₃CH₂)N(CH₃)CH₂)phenyl,2-(((CH₃)₂CH)NHCH₂)phenyl, 2-(((CH₃)₂CH)₂NCH₂)phenyl,2-((cyclopropyl)NHCH₂)phenyl, 2-((cyclopropyl)₂NCH₂)phenyl,2-((cyclobutyl)NHCH₂)phenyl, 2-((cyclobutyl)₂NCH₂)phenyl,2-((cyclopentyl)NHCH₂)phenyl, 2-((cyclopentyl)₂NCH₂)phenyl,2-((cyclohexyl)NHCH₂)phenyl, 2-((cyclohexyl)₂NCH₂)phenyl,1-CH₃-2-imidazolyl, 2-CH₃-1-imidazolyl, 2-((CH₃)₂NCH₂)-1-imidazolyl,2-((CH₃)NHCH₂)-1-imidazolyl, 2-((CH₃CH₂)NHCH₂)-1-imidazolyl,2-((CH₃CH₂)₂NCH₂)-1-imidazolyl, 2-((CH₃CH₂)N(CH₃)CH₂)-1-imidazolyl,2-(((CH₃)₂CH)NHCH₂)-1-imidazolyl, 2-(((CH₃)₂CH)₂NCH₂)-1-imidazolyl,2-((cyclopropyl)NHCH₂)-1-imidazolyl,2-((cyclopropyl)₂NCH₂)-1-imidazolyl, 2-((cyclobutyl)NHCH₂)-1-imidazolyl, 2-((cyclobutyl)₂NCH₂)-1-imidazolyl,2-((cyclopentyl)NHCH₂)-1-imidazolyl,2-((cyclopentyl)₂NCH₂)-1-imidazolyl, 2-((cyclohexyl)NHCH₂)-1-imidazolyl, and2-((cyclohexyl)₂NCH₂)-1-imidazolyl; and, G is selected from4-(methoxy)phenyl, 3-aminoindazol-6-yl, 3-aminophenyl, 2-(aminomethyl)phenyl, 3-(aminomethyl)phenyl,2-(aminomethyl)-3-fluorophenyl, 2-(aminomethyl)-4-fluorophenyl,4-Cl-2-pyridyl, 4-chlorophyll, 3-amino-4-chloro-phenyl,3-amidino-phenyl, 1-aminoisoquinolin-6-yl, 1-aminoisoquinolin-7-yl,4-aminoquinazol-6-yl, 4-aminoquinazol-7-yl, 3-aminobenzisoxazol-5-yl,3-aminobenzisoxazol-6-yl, and 3-aminoindazol-5-yl.
 8. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt form thereof.
 9. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 2 or apharmaceutically acceptable salt form thereof.
 10. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 3 or apharmaceutically acceptable salt form thereof.
 11. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 4 or apharmaceutically acceptable salt form thereof.
 12. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 5 or apharmaceutically acceptable salt form thereof.
 13. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 6 or apharmaceutically acceptable salt form thereof.
 14. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 7 or apharmaceutically acceptable salt form thereof.
 15. A method for treatinga thromboembolic disorder, comprising: administering to a patient inneed thereof a therapeutically effective amount of a compound of claim 1or a pharmaceutically acceptable salt form thereof.
 16. A methodaccording to claim 15, wherein the thromboembolic disorder is selectedfrom the group consisting of arterial cardiovascular thromboembolicdisorders, venous cardiovascular thromboembolic disorders, arterialcerebrovascular thromboembolic disorders, and venous cerebrovascularthromboembolic disorders.
 17. A method according to claim 16, whereinthe thromboembolic disorder is selected unstable angina, firstmyocardial infarction, recurrent myocardial infarction, ischemic suddendeath, transient ischemic attack, stroke, atherosclerosis, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom (a) prosthetic valves or other implants, (b) indwelling catheters,(c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, and (f) otherprocedures in which blood is exposed to an artificial surface thatpromotes thrombosis.
 18. A method for treating a thromboembolicdisorder, comprising: administering to a patient in need thereof atherapeutically effective amount of a compound of claim 2 or apharmaceutically acceptable salt form thereof.
 19. A method according toclaim 18, wherein the thromboembolic disorder is selected from the groupconsisting of arterial cardiovascular thromboembolic disorders, venouscardiovascular thromboembolic disorders, arterial cerebrovascularthromboembolic disorders, and venous cerebrovascular thromboembolicdisorders.
 20. A method according to claim 19, wherein thethromboembolic disorder is selected unstable angina, first myocardialinfarction, recurrent myocardial infarction, ischemic sudden death,transient ischemic attack, stroke, atherosclerosis, venous thrombosis,deep vein thrombosis, thrombophiebitis, arterial embolism, coronaryarterial thrombosis, cerebral arterial thrombosis, cerebral embolism,kidney embolism, pulmonary embolism, and thrombosis resulting from (a)prosthetic valves or other implants, (b) indwelling catheters, (c)stents, (d) cardiopulmonary bypass, (e) hemodialysis, and (f) otherprocedures in which blood is exposed to an artificial surface thatpromotes thrombosis.
 21. A method for treating a thromboembolicdisorder, comprising: administering to a patient in need thereof atherapeutically effective amount of a compound of claim 3 or apharmaceutically acceptable salt form thereof.
 22. A method according toclaim 21, wherein the thromboembolic disorder is selected from the groupconsisting of arterial cardiovascular thromboembolic disorders, venouscardiovascular thromboembolic disorders, arterial cerebrovascularthromboembolic disorders, and venous cerebrovascular thromboembolicdisorders.
 23. A method according to claim 22, wherein thethromboembolic disorder is selected unstable angina, first myocardialinfarction, recurrent myocardial infarction, ischemic sudden death,transient ischemic attack, stroke, atherosclerosis, venous thrombosis,deep vein thrombosis, thrombophlebitis, arterial embolism, coronaryarterial thrombosis, cerebral arterial thrombosis, cerebral embolism,kidney embolism, pulmonary embolism, and thrombosis resulting from (a)prosthetic valves or other implants, (b) indwelling catheters, (c)stents, (d) cardiopulmonary bypass, (e) hemodialysis, and (I) otherprocedures in which blood is exposed to an artificial surface thatpromotes thrombosis.
 24. A method for treating a thromboembolicdisorder, comprising: administering to a patient in need thereof atherapeutically effective amount of a compound of claim 4 or apharmaceutically acceptable salt form thereof.
 25. A method according toclaim 24, wherein the thromboembolic disorder is selected from the groupconsisting of arterial cardiovascular thromboembolic disorders, venouscardiovascular thromboembolic disorders, arterial cerebrovascularthromboembolic disorders, and venous cerebrovascular thromboembolicdisorders.
 26. A method according to claim 25, wherein thethromboembolic disorder is selected unstable angina, first myocardialinfarction, recurrent myocardial infarction, ischemic sudden death,transient ischemic attack, stroke, atherosclerosis, venous thrombosis,deep vein thrombosis, thrombophlebitis, arterial embolism, coronaryarterial thrombosis, cerebral arterial thrombosis, cerebral embolism,kidney embolism, pulmonary embolism, and thrombosis resulting from (a)prosthetic valves or other implants, (b) indwelling catheters, (c)stents, (d) cardiopulmonary bypass, (e) hemodialysis, and (f) otherprocedures in which blood is exposed to an artificial surface thatpromotes thrombosis.
 27. A method for treating a thromboembolicdisorder, comprising: administering to a patient in need thereof atherapeutically effective amount of a compound of claim 5 or apharmaceutically acceptable salt form thereof.
 28. A method according toclaim 27, wherein the thromboembolic disorder is selected from the groupconsisting of arterial cardiovascular thromboembolic disorders, venouscardiovascular thromboembolic disorders, arterial cerebrovascularthromboembolic disorders, and venous cerebrovascular thromboembolicdisorders.
 29. A method according to claim 28, wherein thethromboembolic disorder is selected unstable angina, first myocardialinfarction, recurrent myocardial infarction, ischemic sudden death,transient ischemic attack, stroke, atherosclerosis, venous thrombosis,deep vein thrombosis, thrombophiebitis, arterial embolism, coronaryarterial thrombosis, cerebral arterial thrombosis, cerebral embolism,kidney embolism, pulmonary embolism, and thrombosis resulting from (a)prosthetic valves or other implants, (b) indwelling catheters, (c)stents, (d) cardiopulmonary bypass, (e) hemodialysis, and (f) otherprocedures in which blood is exposed to an artificial surface thatpromotes thrombosis.
 30. A method for treating a thromboembolicdisorder, comprising: administering to a patient in need thereof atherapeutically effective amount of a compound of claim 6 or apharmaceutically acceptable salt form thereof.
 31. A method according toclaim 30, wherein the thromboembolic disorder is selected from the groupconsisting of arterial cardiovascular thromboembolic disorders, venouscardiovascular thromboembolic disorders, arterial cerebrovascularthromboembolic disorders, and venous cerebrovascular thromboembolicdisorders.
 32. A method according to claim 31, wherein thethromboembolic disorder is selected unstable angina, first myocardialinfarction, recurrent myocardial infarction, ischemic sudden death,transient ischemic attack, stroke, atherosclerosis, venous thrombosis,deep vein thrombosis, thrombophlebitis, arterial embolism, coronaryarterial thrombosis, cerebral arterial thrombosis, cerebral embolism,kidney embolism, pulmonary embolism, and thrombosis resulting from (a)prosthetic valves or other implants, (b) indwelling catheters, (c)stents, (d) cardiopulmonary bypass, (e) hemodialysis, and (f) otherprocedures in which blood is exposed to an artificial surface thatpromotes thrombosis.
 33. A method for treating a thromboembolicdisorder, comprising: administering to a patient in need thereof atherapeutically effective amount of a compound of claim 7 or apharmaceutically acceptable salt form thereof.
 34. A method according toclaim 33, wherein the thromboembolic disorder is selected from the groupconsisting of arterial cardiovascular thromboembolic disorders, venouscardiovascular thromboembolic disorders, arterial cerebrovascularthromboembolic disorders, and venous cerebrovascular thromboembolicdisorders.
 35. A method according to claim 34, wherein thethromboembolic disorder is selected unstable angina, first myocardialinfarction, recurrent myocardial infarction, ischemic sudden death,transient ischemic attack, stroke, atherosclerosis, venous thrombosis,deep vein thrombosis, thrombophlebitis, arterial embolism, coronaryarterial thrombosis, cerebral arterial thrombosis, cerebral embolism,kidney embolism, pulmonary embolism, and thrombosis resulting from (a)prosthetic valves or other implants, (b) indwelling catheters, (c)stents, (d) cardiopulmonary bypass, (e) hemodialysis, and (f) otherprocedures in which blood is exposed to an artificial surface thatpromotes thrombosis.